WO2023143393A1 - Tricyclic compound, and preparation method therefor and use thereof - Google Patents

Tricyclic compound, and preparation method therefor and use thereof Download PDF

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WO2023143393A1
WO2023143393A1 PCT/CN2023/073216 CN2023073216W WO2023143393A1 WO 2023143393 A1 WO2023143393 A1 WO 2023143393A1 CN 2023073216 W CN2023073216 W CN 2023073216W WO 2023143393 A1 WO2023143393 A1 WO 2023143393A1
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ring
membered
saturated
independently
alkyl
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PCT/CN2023/073216
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French (fr)
Chinese (zh)
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程建军
汪胜
刘瑞全
祁建忠
樊鲁玉
余竞
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上海科技大学
中国科学院分子细胞科学卓越创新中心
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Publication of WO2023143393A1 publication Critical patent/WO2023143393A1/en

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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to a tricyclic compound, its preparation method and application.
  • GPCRs Monoamine G protein-coupled receptors
  • dopamine receptors such as dopamine receptors, 5-hydroxytryptamine (5-HT) receptors, etc.
  • 5-HT 5-hydroxytryptamine
  • most drugs for antipsychotic and neurodegenerative diseases exert their medicinal effects by regulating the functions of monoamine GPCRs such as dopamine receptors and serotonin receptors.
  • D1-5 dopamine receptors
  • D 1 and D 5 are D 1 type receptors, which are mainly coupled with G s protein, and increase the level of intracellular cyclic adenosine monophosphate (cAMP) after activation
  • D 2 , D 3 , and D 4 are D 2 receptors, which are mainly coupled with G i protein, and reduce intracellular cAMP level after activation.
  • Abnormalities in the dopaminergic signaling pathway are associated with many diseases such as schizophrenia and Parkinson's disease.
  • Small molecule antagonists or partial agonists targeting dopamine D2 receptors are effective antischizophrenic drugs, such as haloperidol, olanzapine, risperidone, aripiprazole, cariprazine (cariprazine) and other main targets are dopamine D2 receptors.
  • the dopamine D3 receptor of the same subfamily as D2 is also an important target of many antischizophrenic drugs (such as cariprazine), and highly selective D3 receptor antagonists or partial agonists also have therapeutic drugs Addictive Potential.
  • D2 receptors are the most widely and deeply studied. According to the intrinsic activity of dopamine D2 receptor ligands, it can be divided into various forms such as agonists, antagonists or partial agonists.
  • Clinically used drugs such as Pramipexole (Pramipexole), Ropinirole (Ropinirole), and Rotigotine (Rotigotine) are agonists of dopamine D2 receptors, which play a therapeutic role by activating dopamine D2 receptors. Treatment of disorders such as Parkinson's disease and restless legs syndrome.
  • Non-classic antischizophrenia drugs such as haloperidol, olanzapine, risperidone, etc.
  • dopamine D2 receptor antagonists which exert their drug effects by antagonizing D2 receptors.
  • the relative affinity of receptors and dopamine D2 receptors is an important basis for distinguishing "typical” and "atypical” drugs. But for many other targets, such as histamine H 1 antagonism, 5-HT 2C receptor antagonism, and drug effects on choline receptors
  • histamine H 1 antagonism such as histamine H 1 antagonism
  • 5-HT 2C receptor antagonism such as 5-HT 2C receptor antagonism
  • drug effects on choline receptors The off-target effect of the body and adrenergic receptors is the reason why most anti-schizophrenia drugs have many side effects, such as causing weight gain and inducing diabetes.
  • the off-target inhibitory effect of some drugs on cholinergic activity is also a possible reason for the further deterioration of cognitive function in patients.
  • 5-HT 2A receptor antagonism is not necessary for the antischizophrenia activity of dopamine D2 receptor partial agonists, and D2 receptor partial agonists that reduce 5-HT 2A receptor antagonism have more Good drug efficacy for improving negative symptoms and cognitive function in schizophrenia (Chen et al., Nat Neurosci 2022, 25, 39–49).
  • 5-HT 1A receptor agonists have shown good clinical application prospects in the treatment of depression, anxiety, and improvement of negative symptoms and cognitive functions in patients with schizophrenia.
  • the agonistic or partial agonistic effect of the drug on the 5-HT 1A receptor can also improve the extrapyramidal side effects of the drug.
  • Atypical antischizophrenia drugs such as aripiprazole, ebiprazole, and cariprazine all have partial agonist effects on 5-HT 1A receptors.
  • Tandospirone for generalized anxiety state Gepirone for antidepressant and anxiolytic effects, Buspirone for anxiety-related symptoms, antidepressant and anti-anxiety Ipsapirone, which has anxiolytic effect, has the pharmacological effect of 5-HT 1A receptor agonist.
  • the 5-HT 1A receptor agonist Flibanserin was approved by the US FDA in 2015 for the treatment of low libido in women.
  • 5-HT 1A receptor agonist or partial agonist is an important direction for the development of new anti-schizophrenia, anti-depression, anti-anxiety and other new drugs.
  • the present invention provides a tricyclic compound, its preparation method and application.
  • the compound of the present invention can be used to treat various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease and the like.
  • the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer or solvate thereof,
  • X is N, O, NR a or CR b ;
  • Y is C or N
  • R a and R b are each independently H or C 1 -C 6 alkyl
  • R c and R d are each independently H or C 1 -C 6 alkyl
  • n1 and n2 are each independently 1, 2, 3, 4, 5 or 6;
  • M is absent, -O- or -NH-C(O)-;
  • Ring Q is a saturated or partially unsaturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or an 8-11 membered Bicyclocyclic rings; one ring in the 8-11 membered bicyclocyclic rings is a saturated or partially unsaturated 5-7-membered carbocycle, or a saturated or partially unsaturated 5-7-membered heterocyclic ring, and the other One ring is a benzene ring or a 5-6 membered heteroaromatic ring;
  • R 1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl
  • R 2 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl or halogenated C 1 -C 6 alkoxy;
  • R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkoxy, -NH-C(O)R e or -NH-S(O) 2 R e ;
  • two R 3 form a 3-8 membered cycloalkyl group with the atoms connected to them;
  • R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
  • R f and R g are each independently C 1 -C 6 alkyl
  • p, q and r are each independently 0, 1, 2, 3 or 4;
  • the number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is 1, 2 or 3 each independently, and each of the heteroatoms is N, O or S independently.
  • Ra and Rb are H.
  • Rc and Rd are H.
  • m is 2, 3 or 4.
  • m is 1.
  • n1 and n2 are 1.
  • L is -( CH2 )-.
  • -NH-C(O)- is attached to L through the N atom.
  • each R 1 is independently C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
  • each R 3 is independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; Preferably, each of R 3 is independently C 1 -C 6 alkyl or -NH-C(O)R e .
  • p is 0.
  • ring Q is linked to M through a C atom.
  • the 3-8 membered carbocycle is a 4, 5, 6 or 7 membered carbocycle.
  • the 3-8 membered heterocycle is a 6-membered heterocycle.
  • the heteroatom in the 3-8 membered heterocyclic ring is N or O, such as N atom.
  • the 6-10 membered aromatic ring is a benzene ring.
  • the number of heteroatoms in the 5-10 membered heteroaromatic ring is 1 or 2.
  • one ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heterocycle.
  • Ring Q is (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).
  • q is 0, 1 or 2.
  • r is 0, 1 or 2.
  • R 3-1 is R 3
  • R 3-2 is H or R 3
  • the definitions of q and R 3 are as described in any scheme of the present invention.
  • each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R e .
  • R 3-1 is hydroxyl
  • each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R.
  • each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R e .
  • each R 3-1 is independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • L is -( CRcRd )- and M is absent.
  • L is -( CRcRd ) 2-
  • M is absent or -NH-C(O)-.
  • L is -(CR c Rd ) 3 - and M is -O-.
  • L is -( CRcRd ) 3- and M is absent .
  • L is -(CR c R d ) 4 - and M is -O-.
  • L is -( CRcRd ) 4- and M is absent .
  • the 3-8 membered carbocycle is a 5-8 membered carbocycle, preferably a 5-7 membered carbocycle, such as a 6-7 membered carbocycle.
  • the 3-8 membered heterocycle is a nitrogen-containing 6-membered heterocycle, such as hexahydropyridine;
  • the 5-10 membered heteroaromatic ring is
  • the 8-11 membered bicyclo is an 8-10 membered bicyclo.
  • the 5-7 membered heterocyclic ring in the 8-11 membered bicyclic ring is saturated or partially unsaturated, and the 5-7 membered heterocyclic ring is 5-6 A membered heterocycle, such as a 6-membered heterocycle.
  • one ring in the 8-11 membered bicyclic ring is saturated or partially unsaturated, and the 5-7 membered heterocycle in the 5-7 membered heterocycle contains at most one N atoms or contain at most one oxygen atom.
  • L is -(CR c R d ) 2 -, and in ring Q, the saturated or partially unsaturated 5-7 membered heterocyclic ring in the 8-11 membered bicyclic ring contains at most a N.
  • L is -(CR c R d ) 4 -
  • M is -O-
  • the benzene ring in the 8-11 membered bicyclic ring or the 5-6 membered heteroaryl ring is 5- 6-membered aromatic heterocycle.
  • ring Q is a saturated 3-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered heteroaryl ring, or an 8- 11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or a saturated or partially unsaturated 5-7-membered heterocyclic ring , and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.
  • Ring Q is a saturated 3-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, a 5-10 membered heteroaryl ring, or an 8-10 membered bicyclic and Ring; one ring in the 8-10 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is A benzene ring or a 5-6 membered heteroaromatic ring.
  • the compound represented by the formula I has any of the following structures:
  • the compound is any of the following:
  • X is N, O, NR a or CR b ;
  • Y is C or N
  • Rc and Rd are each independently H
  • n 1, 2, 3 or 4;
  • n1 and n2 are 1;
  • r 0, 1 or 2;
  • q 0, 1 or 2;
  • M is absent, -O- or -NH-C(O)-;
  • Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, a 6-10-membered aromatic ring, a 5-10-membered heteroaromatic ring or an 8-11-membered bicyclic ring ;
  • One ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is benzene Ring or 5-6 membered heteroaromatic ring;
  • R 1 is C 1 -C 6 alkyl
  • R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; preferably, R 3 are each independently hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 are connected to the atom to form 3-8 Cycloalkyl;
  • R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
  • R f and R g are each independently C 1 -C 6 alkyl
  • the number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is 1, 2 or 3 each independently, and each of the heteroatoms is N, O or S independently.
  • Rc and Rd are each independently H
  • n 1, 2, 3 or 4;
  • n1 and n2 are 1;
  • r 0, 1 or 2;
  • q 0, 1 or 2;
  • M is absent, -O- or -NH-C(O)-;
  • Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, phenyl, a 5-10-membered heteroaryl ring or an 8-10-membered Bicyclocyclic rings; one ring in the 8-10 membered bicyclocyclic rings is a saturated or partially unsaturated 5-7-membered carbocyclic ring, or a saturated or partially unsaturated 5-6-membered heterocyclic ring, and the other One ring is a benzene ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, two nitrogen atoms, or, an oxygen atom and a nitrogen atom;
  • R 1 is C 1 -C 6 alkyl
  • R 3 is hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 and the atoms connected to it form a 3-8 membered Cycloalkyl;
  • R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
  • R f and R g are each independently C 1 -C 6 alkyl
  • heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
  • X is N or O
  • Y is C
  • r 0, 1 or 2;
  • q 0, 1 or 2;
  • L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
  • ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-7 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
  • Ring Q is a partially unsaturated 3-8 membered heterocycle or 8-11 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-7 membered heterocyclic ring, the other ring is a benzene ring;
  • ring Q is an 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
  • R 1 is C 1 -C 6 alkyl
  • Each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O) Re ; preferably, each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
  • R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
  • R f and R g are each independently C 1 -C 6 alkyl
  • the number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently Ground is N, O or S;
  • the 5-7 membered heterocycle in the saturated or partially unsaturated 5-7 membered heterocycle in the 8-11 membered bicyclic ring contains one oxygen atom, one nitrogen atom, two oxygen atoms, or, an oxygen atom and a nitrogen atom;
  • X is N or O
  • Y is C
  • r 0, 1 or 2;
  • q 0, 1 or 2;
  • L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
  • ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-6 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
  • ring Q is a partially unsaturated 3-8 membered heterocycle or 8-10 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-6 membered heterocyclic ring, the other ring is a benzene ring;
  • ring Q is an 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-6-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
  • the ring Q is a saturated or partially unsaturated 3-8 membered heterocycle or an 8-10 membered bicyclic ring; one of the 8-6 membered bicyclic rings
  • the ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring;
  • R 1 is C 1 -C 6 alkyl
  • Each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
  • R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
  • R f and R g are each independently C 1 -C 6 alkyl
  • heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
  • the 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, or, an oxygen atom and an Nitrogen atom;
  • X is O; Y is C; P is 0;
  • L is -(CR c R d ) m -, when m is 1, M does not exist, the ring Q is a saturated 6-membered carbon ring, and R 3 is a hydroxyl group;
  • L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 3-8 membered carbocycle, hexahydropyridine, thiophene, benzene group, each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e , and R e is a C 1 -C 6 alkyl group;
  • L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
  • L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine,
  • each R 3 is independently C 1 -C 6 alkyl
  • Ring Q is When , q is 0;
  • R 1 is C 1 -C 6 alkyl
  • L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 5-7 membered carbon ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
  • L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
  • R 1 is methyl
  • L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
  • L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
  • X is O; Y is C; P is 0;
  • L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 4;
  • L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 6-7-membered carbocycle, phenyl, 8-11-membered Bicyclic rings; one ring in the 8-11-membered bicyclic rings is a saturated 5-7-membered heterocyclic ring, and the other ring is a 5-6-membered heteroaromatic ring; the 5-6-membered Heteroaromatic rings contain one or two nitrogen atoms;
  • L is -(CR c R d ) m -, when m is 4, M is absent or -O-;
  • L is -(CR c R d ) m -, m is 4, and when M is absent, ring Q is a partially unsaturated 6-membered heterocyclic ring or
  • the heteroatom in the partially unsaturated 6-membered heterocyclic ring is a nitrogen atom, and the number of heteroatoms is 1, 2 or 3 independently;
  • R 3 is each independently F, C 1 -C 6 alkyl, -NH-C(O)R e , and R e is C 1 -C 6 alkyl.
  • X is O; Y is C; P is 0;
  • L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-6 membered carbocycle, thiophene, phenyl, R 3
  • Each is independently C 1 -C 6 alkyl, -NH-C(O)R e , Re is C 1 -C 6 alkyl;
  • L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine, q is 0;
  • R 1 is C 1 -C 6 alkyl
  • L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 3;
  • L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 6-membered carbocyclic ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
  • L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
  • R 1 is methyl
  • L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
  • L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
  • the compound represented by the formula I has any of the following structures:
  • the present invention also provides a preparation method of the compound shown in formula I, which comprises the following steps: in a solvent (such as a mixed solvent of N,N-dimethylformamide and water), combining the compound shown in formula II with formula III
  • a solvent such as a mixed solvent of N,N-dimethylformamide and water
  • the compound shown is subjected to the following coupling reaction to obtain the compound shown in formula I;
  • Hal is a halogen (such as Br); the definitions of other variables are as described in any scheme of the present invention.
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I or its pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereoisomer, tautomer Isomers or solvates, and pharmaceutically acceptable excipients.
  • the present invention also provides a use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating mental diseases or neurodegenerative diseases.
  • the present invention also provides a compound represented by the above-mentioned formula I or its pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereoisomer, tautomer or solvent Use of compounds in the preparation of medicines for treating mental illnesses or neurodegenerative diseases.
  • the psychiatric or neurodegenerative disease is schizophrenia, depression, or Parkinson's disease.
  • substituted or "substituent” is a group in which a hydrogen atom is replaced by the designated group.
  • substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on the ring A is replaced by m R 1 , in addition, when the ring A is bicyclic and ring When , any ring in the bicyclic ring can be substituted, for example, unless otherwise specified, The structure indicates that the hydrogen atoms on ring A1 and/or ring A2 are replaced by m R1 .
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is absent, it means that the linking group is a single bond, for example, the structure formed when L is absent in A-L-Z is A-Z.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C 1 -C 6 alkyl refers to an alkyl group having 1-6 carbon atoms, which is preferably C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl or tert-butyl.
  • haloalkyl refers to a group formed by replacing one or more (for example, 2, 3, 4, 5 or 6) hydrogen atoms in the alkyl group with halogen, wherein each halogen is independently F, Cl, Br or I.
  • Halogenated C 1 -C 6 alkyl refers to C 1 -C 6 alkyl substituted by one or more halogens, wherein the definition of C 1 -C 6 alkyl is as described above.
  • alkoxy refers to -O-alkyl, wherein the definition of alkyl is as described above.
  • C 1 -C 6 alkoxy refers to -O-(C 1 -C 6 alkyl), wherein the definition of C 1 -C 6 alkyl is as described above.
  • the term "carbocycle” refers to a saturated, partially unsaturated or aromatic monocyclic or polycyclic (eg, asymmetric, spiro or bridged) cyclic group formed of carbon atoms.
  • a saturated carbocycle each carbon atom on the ring is saturated.
  • saturated carbocycles include, but are not limited to In an aromatic carbocycle, each ring is aromatic, examples of aromatic carbocycles include, but are not limited to In a partially unsaturated carbocycle, at least one carbon atom in the ring is saturated and at least one carbon atom is unsaturated.
  • Examples of partially unsaturated carbocycles include, but are not limited to The 3-8 membered carbocycle can specifically be 3, 4, 5, 6, 7 or 8 membered carbocycle.
  • heterocycle refers to a saturated, partially unsaturated or aromatic monocyclic or polycyclic (such as a ring, spiro or bridged ring) cyclic group formed by carbon atoms and at least one heteroatom A group wherein the heteroatoms are independently selected from N, O and S.
  • a saturated heterocyclic ring both the carbon atoms and the heteroatoms on the ring are saturated
  • examples of saturated heterocyclic rings include but are not limited to In aromatic heterocycles, each ring is aromatic
  • examples of aromatic heterocycles include but are not limited to In a partially unsaturated heterocyclic ring, at least one atom of the ring is saturated and at least one atom is unsaturated.
  • Examples of partially unsaturated heterocyclic rings include, but are not limited to Specifically, the 3-8 membered heterocycle can be 3, 4, 5, 6, 7 or 8 membered heterocycle.
  • the 5-7 membered heterocycle may specifically be a 5, 6 or 7 membered heterocycle.
  • aromatic ring refers to an aromatic carbocyclic ring in which each ring is aromatic.
  • the 6-10 membered aromatic ring may be a benzene ring or a naphthalene ring.
  • heteroaromatic ring refers to an aromatic heterocyclic ring in which each ring is aromatic.
  • heteroaromatic rings include, but are not limited to The 5-10 membered heteroaryl ring can specifically be a 5, 6, 7, 8, 9 or 10 membered heteroaryl ring.
  • bicyclic double ring refers to a double ring composed of two single rings, and its connection site with other structures can be located on any single ring.
  • the 8-11 membered bicyclo can be specifically 8, 9, 10 or 11 membered bicyclo.
  • cycloalkyl refers to a monocyclic or polycyclic (eg fused, spiro or bridged) monovalent hydrocarbon group in which each carbon atom is saturated.
  • the 3-8 membered cycloalkyl group can specifically be 3, 4, 5, 6, 7 or 8 membered cycloalkyl groups, including cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, etc.
  • Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the compounds of the present invention and their structures also represent all isomers (including stereoisomers and tautomers, wherein stereoisomers such as enantiomers, diastereomers, geometric isomers isomers (such as cis-trans isomers) and conformational isomers) forms. They can be defined according to the absolute stereochemistry for amino acids as (R)-/(S)- or (D)-/(L)- or (R,R)-/(R,S)-/(S,S) -.
  • the present invention includes all such possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms.
  • Optical rotation (+) and (-), (R)- and (S)- and (R,R)-/(R,S)-/(S,S)- or (D)- and (L)-iso Constructs can be prepared using chiral starting materials synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using chiral columns.
  • HPLC high performance liquid chromatography
  • the compounds described herein contain alkenyl double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds include both E and Z geometric isomers.
  • chemical structure, bond configuration is not specified, i.e. if there is configurational isomerism in the chemical structure, the bond can be or both Two configurations. Likewise, all tautomeric forms are also included.
  • tautomer refers to the movement of a proton from one atom of a molecule from its original position to another position of the same molecule.
  • the present invention includes tautomers of any of said compounds.
  • isotopically derivative refers to a compound whose structure differs only by the presence of one or more isotopically enriched atoms.
  • having the structure of the present invention except replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with 18 F-fluorine label ( 18 F isotope), or replacing fluorine with 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace the carbon atoms are within the scope of the invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the isotopic derivatives are, for example, deuterated compounds.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing Adverse biological reaction or interaction in an adverse manner with any component contained in the composition.
  • the term "pharmaceutically acceptable salt” means a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with a compound, which retains the biological activity of the compound.
  • Described organic acid can be various organic acids that can form salt conventionally in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid, and salicylic acid.
  • the inorganic acid may be various inorganic acids conventional in the art capable of forming salts, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic base can be various organic bases that are conventional in the art and can form salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines kind.
  • the tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine.
  • the aniline organic base is preferably N,N-dimethylaniline.
  • the pyridine organic base is preferably pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine One or more of pyridines.
  • Described inorganic base can be various inorganic bases that can form salt conventionally in the art, preferably alkali metal hydride, hydroxide of alkali metal, alkoxide of alkali metal, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate One or more of , potassium bicarbonate and sodium bicarbonate.
  • the alkali metal hydride is preferably sodium hydride and/or potassium hydride.
  • the hydroxide of the alkali metal is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
  • solvate means a compound or a salt thereof with a suitable solvent.
  • the solvent is preferably water or an organic solvent.
  • the term "patient” includes any animal, preferably a mammal, more preferably a human.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound of the present invention has excellent pharmacological effects on various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease, etc., so it can be used as an effective drug for treating the above diseases .
  • the overnight reaction is 12-18 hours.
  • Example 1 Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-quinoline- Preparation of 2(1H)-ketone (I-A1)
  • Step 1 Synthesis of LRQ-04-148 refers to patent WO2006064355A2.
  • HRMS (ESI ) Calcd. for C11H10NO2 + [M+H] + : 188.0706, found: 188.0702.
  • Step 2 Synthesis of LRQ-04-149 refers to patent WO2006064355A2.
  • Step 3 LRQ-04-149 (500 mg, 2.62 mmol) and Et 3 N (796 mg, 7.86 mmol) were dissolved in dichloromethane (10 mL), (Boc) 2 O (714mg, 3.27mmol) was added and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain LRQ-04-150 as a white solid. Purified directly into the next reaction. HRMS (ESI) calcd for C16H22NO4 + [M+H] + : 292.1543 , found : 292.1549.
  • Step 4 After LRQ-04-150 and paraformaldehyde (157mg, 5.24mmol) were dissolved in toluene (10mL), p-toluenesulfonic acid (25mg, 0.13mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain LRQ-04-151 as a white solid. Purified directly into the next reaction. HRMS (ESI) calcd for C17H22NO4 + [M+H] + : 304.1543 , found : 304.1545.
  • Step 5 LRQ-04-151 was dissolved in 4M hydrogen chloride in dioxane solution (8 mL), and reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then filtered with suction, the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-04-153 (202 mg, Three-step reaction yield 38%).
  • Step 6 After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C.
  • Example 2 Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-A2)
  • Step 1 After dissolving 6-hydroxyindolin-2-one (2.17g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutyl Alkanes (9.42g, 43.65mmol), react overnight at room temperature.
  • Step 1 After dissolving 7-hydroxy-1-methylquinolin-2(1H)-one (2.55g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol) successively, 1,4-Dibromobutane (9.42g, 43.65mmol), react overnight at room temperature.
  • K 2 CO 3 2.1g, 14.55mmol
  • 1,4-dibromobutane 9.42g, 43.65mmol
  • Example 7 Compound 2-(4-(benzo[d]thiazol-5-yloxy)butyl)-8-methoxy-1,2,3,4-tetrahydrobenzofurano[2, 3-c] Preparation of pyridine (I-A7)
  • Step 1 After dissolving 5-hydroxybenzothiazole (2.20g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutane (9.42g , 43.65mmol), react overnight at room temperature.
  • Example 8 Compound 7-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propoxy)quinoline-2 Preparation of (1H)-ketone (I-A8)
  • Example 9 Compound 7-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-A9)
  • Example 11 Compound N-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl) ) cyclohexyl) acetamide (I-A11) preparation
  • Step 1 After dissolving NaOH (62mg, 1.56mmol) in H 2 O (10mL), add K 2 CO 3 (440mg, 3.16mmol), trans-(N-BOC-4-aminocyclohexyl)acetic acid ( 200mg, 0.78mmol) and benzyl bromide (540mg, 3.16mmol), reflux for 3 hours.
  • Step 2 Dissolve LRQ-04-11 (200mg, 0.63mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (1.9mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (5 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a white solid LRQ- 04-12-Boc, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C13H26NO3 + [M+H] + : 244.1907 , found : 244.1910.
  • Step 3 Dissolve LRQ-04-12-Boc in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (500mg, 1.41mmol) and triphenylphosphine (500mg, 1.88mmol) in sequence, and react overnight at room temperature .
  • Step 4 Dissolve LRQ-04-152-Boc (113mg, 0.38mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid LRQ-04-12-NH2, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C8H17BrN + [M+H] + : 206.0539, found : 206.0541.
  • Step 5 After LRQ-04-12-NH2 was dissolved in DCM (10 mL), triethylamine (115 mg, 1.14 mmol) and acetyl chloride (33 mg, 0.42 mmol) were added successively, and reacted overnight at room temperature.
  • Example 12 Compound 3-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A12)
  • Step 1 Dissolve LRQ-04-12-NH2 in DCM (10mL), add triethylamine (115mg, 1.14mmol) and dimethylcarbamoyl chloride (45mg, 0.42mmol) successively, and react overnight at room temperature.
  • Example 13 Compound N-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) methanesulfonamide (I-A13) preparation
  • Step 1 After LRQ-04-12-NH2 was dissolved in DCM (10 mL), triethylamine (115 mg, 1.14 mmol) and methanesulfonyl chloride (48 mg, 0.42 mmol) were added successively, and reacted overnight at room temperature.
  • Step 1 After dissolving LRQ-04-153 (340mg, 1.67mmol) and DIPEA (1.3g, 10.02mmol) in DMF (10mL), add N-Boc-2-bromoethylamine (561mg, 2.51mmol), React overnight at 100°C.
  • Step 2 Dissolve LRQ-05-116 (70mg, 0.20mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol), react overnight at room temperature.
  • Example 15 Compound 4,4-difluoro-N-(2-(8-methoxy-3,4-dihydrobenzofur[2,3-c]pyridin-2(1H)-yl)ethyl Base) the preparation of cyclohexane-1-carboxamide (I-A15)
  • LRQ-05-116 (70mg, 0.20mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol), react overnight at room temperature.
  • Step 1 After dissolving methyl 2-(7-hydroxybenzofuran-3-yl)acetate (2.0 g, 9.70 mmol) and K 2 CO 3 (1.3 g, 9.70 mmol) in DMF (10 mL), add iodine Ethane (4.54g, 29.10mmol), stirred at room temperature overnight.
  • Step 2 Dissolve LRQ-05-125 (2.2g, 9.40mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (28.2mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours.
  • Step 3 After dissolving LRQ-05-127 (1.5g, 7.28mmol), triphenylphosphine (2.86g, 10.92mmol) and phthalimide (1.61g, 10.92mmol) in tetrahydrofuran (50mL) , cooled to 0° C., and added DEAD (1.90 g, 10.92 mmol). Then the reaction solution was warmed to room temperature and reacted overnight.
  • Step 4 After LRQ-05-129 was dissolved in a mixed solution of methanol (80 mL) and dichloromethane (20 mL), hydrazine hydrate (911 mg, 18.2 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain LRQ-05-131, a light yellow oily liquid, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C12H16NO2 + [M+H] + : 206.1176, found : 206.1182 .
  • Step 5 After dissolving LRQ-05-131 and Et 3 N (2.21 g, 21.84 mmol) in dichloromethane (10 mL), add (Boc) 2 O (1.99 g, 9.10 mmol) and react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05- 133, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C17H24NO4 + [M+H] + : 306.1700 , found : 306.1703.
  • Step 6 After LRQ-05-133 and paraformaldehyde (437mg, 14.56mmol) were dissolved in toluene (20mL), p-toluenesulfonic acid (88mg, 0.51mmol) was added, and the reaction was refluxed overnight.
  • Step 7 LRQ-05-135 (750 mg, 2.36 mmol) was dissolved in 4M hydrogen chloride in dioxane (10 mL), and reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then filtered with suction, the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-05-137 (436 mg, Yield 85%).
  • Step 8 After dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol), 7-(4-bromobutoxy)quinolin-2(1H)-one (103mg, 0.35mmol), react overnight at 100°C.
  • Example 17 Compound 3-(trans-4-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A17)
  • Example 18 Compound 7-(4-(8-isopropoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)quinoline- Preparation of 2(1H)-ketone (I-A18)
  • Step 1 After dissolving methyl 2-(7-hydroxybenzofuran-3-yl)acetate (2.0 g, 9.70 mmol) and K 2 CO 3 (1.3 g, 9.70 mmol) in DMF (10 mL), add 2 -Bromopropane (3.58g, 29.10mmol), stirred at room temperature overnight.
  • Step 2 Dissolve LRQ-05-126 (2.3g, 9.50mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (28.5mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours.
  • Step 3 After dissolving LRQ-05-128 (1.6g, 7.32mmol), triphenylphosphine (2.88g, 10.97mmol) and phthalimide (1.61g, 10.97mmol) in tetrahydrofuran (50mL) , cooled to 0° C., and added DEAD (1.91 g, 10.97 mmol). Then the reaction solution was warmed to room temperature and reacted overnight.
  • Step 4 After LRQ-05-130 was dissolved in a mixed solution of methanol (80 mL) and dichloromethane (20 mL), hydrazine hydrate (916 mg, 18.3 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain an orange-yellow solid LRQ-05-132, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C13H18NO2 + [M+H] + : 220.1332 , found : 220.1336.
  • Step 5 After dissolving LRQ-05-132 and Et 3 N (2.22 g, 21.96 mmol) in dichloromethane (10 mL), add (Boc) 2 O (2.00g, 9.15mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05- 134, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C18H26NO4 + [M+H] + : 320.1856 , found : 320.1858.
  • Step 6 After dissolving LRQ-05-134 and paraformaldehyde (440 mg, 14.64 mmol) in toluene (20 mL), p-toluenesulfonic acid (88 mg, 0.51 mmol) was added, and the reaction was refluxed overnight.
  • Step 7 LRQ-05-136 (890 mg, 2.69 mmol) was dissolved in 4M hydrogen chloride in dioxane (10 mL), and reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then suction filtered, and the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-05-138 (577 mg, Yield 83%).
  • Step 8 After dissolving LRQ-05-138 (50mg, 0.22mmol) in DMF (8mL), add DIPEA (171mg, 1.32mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (97mg, 0.33mmol), react overnight at 100°C.
  • Example 19 Compound 3-(trans-4-(2-(8-isopropoxy-3,4-dihydrobenzofur[2,3-c]pyridin-2(1H)-yl)B base) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A19)
  • Example 20 Compound 7-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)quinoline-2( Preparation of 1H)-ketone (I-A20) (IHCH-5219)
  • Step 1 dissolve methyl 3-aminobenzenebutyrate (1.00g, 5.17mmol) in dichloromethane (10mL), cool down to 0°C, add pyridine (818mg, 10.34mmol) and cinnamoyl chloride (1.29g, 7.76 mmol), warmed up to room temperature and reacted overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10mL), extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain an orange-yellow oily liquid LRQ-06- 95, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C20H22NO3 + [M+H]+: 324.1594, found : 324.1597 .
  • Step 3 LRQ-06-96 (780mg, 3.18mmol) was dissolved in THF (20mL), the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (10mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction is complete, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain a yellow oily liquid LRQ-06-97, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C13H16NO2 + [M+H]+: 218.1176, found : 218.1178 .
  • Step 4 Dissolve LRQ-06-97 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.58g, 4.77mmol) and triphenylphosphine (1.67g, 6.36mmol) in sequence, and react overnight at room temperature .
  • Example 21 Compound 1-((8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)methyl)cyclohexane-1-ol Preparation of (I-A21)(IHCH-5228)
  • Example 22 Compound 2-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A22)(IHCH-5201)
  • Step 1 after dissolving 4-methyl-2H-[1,2,4]triazine-3,5-dione (2.25g, 17.70mmol) in DMF (20mL), add NaH (0.85g, 21.24 mmol), 1,4-dibromobutane (11.46g, 53.10mmol), react overnight at room temperature.
  • Example 23 Compound 2-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A23)(IHCH-5202)
  • Step 1 after dissolving 4-methyl-2H-[1,2,4]triazine-3,5-dione (2.25g, 17.70mmol) in DMF (20mL), add NaH (0.85g, 21.24 mmol), 1,3-dibromopropane (11.25g, 53.10mmol), react overnight at room temperature.
  • Example 24 Compound 1-(2-(-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1,3-di Preparation of Hydrogen-2H-Benzo[d]imidazol-2-one(I-A24)(IHCH-5223)
  • Example 25 Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)quinoline-2( Preparation of 1H)-ketone (I-A25) (IHCH-5225)
  • Example 26 Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)quinoline-2( Preparation of 1H)-ketone (I-A26) (IHCH-5218)
  • Step 1 dissolve methyl 3-aminophenylpropionate (1.00g, 5.58mmol) in dichloromethane (10mL), cool down to 0°C, add pyridine (883mg, 11.16mmol) and cinnamoyl chloride (1.39g, 8.37mmol), warming up to room temperature and reacting overnight. After completion of the reaction, add saturated aqueous sodium bicarbonate solution (10mL) to dilute, extract with ethyl acetate (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a colorless oily liquid LRQ-06 -89, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C19H20NO3 + [M+H]+: 310.1438 , found : 310.1438.
  • Step 3 LRQ-06-90 (520mg, 2.25mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (7mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-91, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C12H14NO2 + [M+H] + : 204.1019 , found : 204.1024.
  • Step 4 Dissolve LRQ-06-91 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.12g, 3.38mmol) and triphenylphosphine (1.18g, 4.50mmol) in sequence, and react overnight at room temperature .
  • Example 27 Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)quinoline-2( Preparation of 1H)-ketone (I-A27) (IHCH-5217)
  • Step 1 dissolve methyl 3-aminophenylacetic acid (1.00g, 6.05mmol) in dichloromethane (10mL), after cooling down to 0°C, add pyridine (957mg, 12.10mmol) and cinnamoyl chloride (1.52g, 9.08 mmol), warming up to room temperature and reacting overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10mL), extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain brown-yellow oily liquid LRQ-06- 82, directly used in the next reaction without purification.
  • HRMS (ESI) calcd for C18H18NO3 + [M+H]+: 296.1281, found : 296.1288.
  • Step 3 LRQ-06-84 (560mg, 2.57mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-85, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C11H12NO2 + [M+H]+: 190.0863, found : 190.0865 .
  • Step 4 Dissolve LRQ-06-85 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.28g, 3.86mmol) and triphenylphosphine (1.35g, 5.14mmol) in sequence, and react overnight at room temperature .
  • Example 28 Compound 1-((8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)methyl)cyclohexane-1-ol Preparation of (I-A28)(IHCH-5232)
  • Example 29 Compound 7-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-1,8 - Preparation of naphthyridin-2(1H)-one (I-A29) (IHCH-5213)
  • Step 1 after cooling concentrated sulfuric acid (6mL) to 0°C, add 2-amino-7-hydroxyl-1,8-naphthyridine (1.00g, 6.21mmol) and sodium nitrite (684mg, 9.92mmol) successively, and react After 15 minutes, the temperature was raised to room temperature and the reaction was continued for 15 minutes. After the reaction was completed, pour it into ice water, add saturated aqueous sodium bicarbonate solution to adjust the pH to 8, extract with ethyl acetate (50mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a gray-brown solid LRQ-06-64, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C8H7N2O2 + [M+H]+: 163.0502, found : 163.0507.
  • Step 2 after dissolving LRQ-06-64 in DMF (20mL), add K 2 CO 3 (858mg, 6.21mmol) and 1,4-dibromobutane (2.68g, 12.42mmol) sequentially, and react overnight at room temperature .
  • Example 30 Compound 6-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-2H-benzene and[b][1,4] Preparation of Oxazin-3(4H)-one(I-A30)(IHCH-5194)
  • Step 1 after dissolving 6-hydroxy-2H-1,4-benzoxazin-3(4H)-one (0.3g, 1.77mmol) in DMF (10mL), add K 2 CO 3 (0.25g, 1.77 mmol), 1,4-dibromobutane (1.15g, 5.31mmol), react overnight at room temperature.
  • Example 31 Compound 2-(3-(Benzo[d][1,3]diox-5-yloxy)propyl)-8-ethoxy-1,2,3,4-tetrahydro Preparation of Benzofuro[2,3-c]pyridine(I-A31)(IHCH-5193)
  • Step 1 after dissolving sesamol (1.00g, 7.23mmol) in DMF (10mL), adding K 2 CO 3 (1.00g, 7.23mmol), 1,3-dibromopropane (4.39g, 21.72mmol) in sequence, React overnight at room temperature.
  • Example 32 Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cycloheptanecarboxamide Preparation of (I-A32)(IHCH-5215)
  • LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and cycloheptanecarbonyl chloride (46mg, 0.28mmol), and reacted at room temperature overnight.
  • Example 33 Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cyclopentanecarboxamide (I- A33) Preparation of (IHCH-5214)
  • LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and cyclopentylformyl chloride (40mg, 0.28mmol), and reacted at room temperature overnight.
  • Example 34 Compound 3-(3-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cyclobutane base)-1,1-dimethylurea (I-A34) (IHCH-5195)
  • Step 2 after dissolving LRQ-05-148 (2.00 g, 8.30 mmol) in anhydrous methanol (20 mL), add 10% palladium carbon, replace with hydrogen three times, pass in hydrogen, and react overnight at room temperature. After the reaction was completed, it was filtered, and the solvent was evaporated under reduced pressure to obtain a white solid LRQ-05-149, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C12H22NO4 + [M+H]+: 244.1543 , found : 244.1546.
  • Step 3 Dissolve LRQ-05-149 in THF (20 mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (25 mL, 1.0 M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05-150, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C11H12NO3 + [M+H]+: 216.1594 , found : 216.1589.
  • Step 4 Dissolve LRQ-05-150 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (2.79g, 8.41mmol) and triphenylphosphine (2.94g, 11.21mmol) in sequence, and react overnight at room temperature .
  • Step 5 LRQ-06-03 (250mg, 1.41mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a light yellow oily liquid LRQ-06-03-NH2, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C6H13BrN + [M+H]+: 178.0226, found: 178.0227 .
  • Step 6 after dissolving LRQ-06-03-NH2 in DCM (10mL), triethylamine (428mg, 4.23mmol) and dimethylcarbamoyl chloride (182mg, 1.69mmol) were added successively, and reacted overnight at room temperature.
  • LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), added DIPEA (150 mg, 1.16 mmol) and benzoyl chloride (40 mg, 0.28 mmol), and reacted overnight at room temperature.
  • Example 36 Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)thiophene-2-methan Preparation of Amide (I-A36) (IHCH-5211)
  • Step 1 After dissolving LRQ-05-137 (320mg, 1.48mmol) in DMF (10mL), add DIPEA (1.15g, 8.88mmol) and N-Boc-2-bromoethylamine (498mg, 2.22mmol) in sequence , react overnight at 100°C.
  • Step 2 Dissolve LRQ-06-67 (70mg, 0.19mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and 2-thiophenoyl chloride (42mg, 0.28mmol), and reacted at room temperature overnight.
  • DIPEA 150mg, 1.16mmol
  • 2-thiophenoyl chloride 42mg, 0.28mmol
  • Example 37 Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-3,4- Preparation of Dihydroisoquinolin-1(2H)-one(I-A37)(IHCH-5198)
  • Step 1 Dissolve 3,4-dihydroisoquinolin-1(2H)-one (526mg, 3.57mmol) in toluene (10mL) and cool down to 0°C, add NaH (167mg, 4.18mmol), reflux reaction 1 Hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (639 mg, 4.18 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 2 LRQ-06-23 (526mg, 2.40mmol) was dissolved in THF (10mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (7mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-24, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C11H14NO2 + [M+H]+: 192.1019 , found : 192.1015.
  • Step 3 Dissolve LRQ-06-24 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.19g, 3.60mmol) and triphenylphosphine (1.26g, 4.80mmol) in sequence, and react overnight at room temperature .
  • Example 38 Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-6-methyl Preparation of -3,4-trihydro-2,7-naphthyridin-1(2H)-one (I-A38)(IHCH-5199)
  • Step 1 methyl 4-chloro-6-methylnicotinate (4.03g, 21.78mmol), tributylvinyltin (10.36g, 32.67mmol) and tetrakis(triphenylphosphine) palladium (1.76g , 1.52 mmol) was dissolved in toluene (10 mL) and 1,4-dioxane (10 mL), and after nitrogen replacement three times, the temperature of the reaction solution was raised to 90° C. to react overnight. After the reaction was completed, dilute with saturated aqueous sodium bicarbonate solution (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 2 after mixing LRQ-06-05 (3.20g, 18.08mmol) and 50ml ammonia (50mL, 7.0M methanol solution) in a sealed tube, the reaction solution was heated to 100°C and stirred overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a pink solid LRQ-06-06, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C9H11N2O + [M+H]+: 163.0866 , found: 163.0869 .
  • Step 3 Dissolve LRQ-06-06 in toluene (10 mL) and cool down to 0°C, add NaH (844 mg, 21.17 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (3.23 g, 21.17 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 4 LRQ-06-25 (600mg, 2.56mmol) was dissolved in THF (10mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-26, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C11H15N2O2 + [M+H]+: 207.1128 , found : 207.1130.
  • Step 5 Dissolve LRQ-06-26 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.27g, 3.84mmol) and triphenylphosphine (1.34g, 5.12mmol) in sequence, and react overnight at room temperature .
  • Example 39 Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-2,3- Preparation of Dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (I-A39)(IHCH-5216)
  • Step 1 methyl 3-bromo-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.46g, 2.04mmol), 2((tert-butoxycarbonyl)amino)ethyltrifluoroboronic acid Potassium (0.76g, 3.04mmol), cesium carbonate (1.64g, 5.06mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex ( 0.16g, 0.18mmol) was dissolved in toluene (16mL) and water (8mL), and after nitrogen replacement three times, the temperature of the reaction solution was raised to 100°C for 3 hours.
  • Step 2 Dissolve LRQ-06-71 in DCM (10 mL) and cool down to 0° C., add trifluoroacetic acid (1 mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a light yellow oily liquid LRQ-06-71-NH2, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C9H16N3O2 + [M+H]+: 198.1237 , found : 198.1239.
  • Step 3 after dissolving LRQ-06-71-NH2 in methanol (10mL), add sodium methoxide (2mL, 5.0M methanol solution) to react at room temperature for 0.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, diluted with water (10mL), extracted with dichloromethane (20mL*3), washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain LRQ-06-72 as a light yellow solid. Purified directly into the next reaction. HRMS ( ESI ) calcd. for C8H12N3O + [M+H]+: 166.0975 , found: 166.0969.
  • Step 4 Dissolve LRQ-06-72 in toluene (10 mL) and cool down to 0°C, add NaH (94 mg, 2.36 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, ethyl bromoacetate (394 mg, 2.36 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 5 LRQ-06-75 (220mg, 0.87mmol) was dissolved in THF (5mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (3mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. reaction After completion, add saturated potassium sodium tartrate aqueous solution (10mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain light yellow oily liquid LRQ -06-77, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C10H16N3O2 + [M+H]+: 210.1237 , found : 210.1238.
  • Step 6 Dissolve LRQ-06-77 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (432mg, 1.31mmol) and triphenylphosphine (456mg, 1.74mmol) in sequence, and react overnight at room temperature.
  • Example 40 Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-2,3, 4,5-Tetrahydro-1H-benzo[c]azepine Preparation of -1-ketone (I-A40) (IHCH-5209)
  • Step 1 the 2,3,4,5-tetrahydro-1H-2-benzazepine -1-Kone (1.00g, 6.20mmol) was dissolved in toluene (10mL) and cooled to 0°C, NaH (290mg, 7.26mmol) was added and refluxed for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.11 g, 7.26 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 2 LRQ-06-49 (1.00g, 4.30mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (13mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-52, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C12H16NO2 + [M+H]+: 206.1176, found : 206.1180 .
  • Step 3 Dissolve LRQ-06-52 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (2.14g, 6.45mmol) and triphenylphosphine (2.26g, 8.60mmol) in sequence, and react overnight at room temperature .
  • Example 41 Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1-methyl -5,6,7,8-Tetrahydropyrrole[3,2-c]azepine - Preparation of 4(1H)-1-one (I-A41) (IHCH-5210)
  • Step 1 after dissolving azepane-2,4-dione (1.00g, 7.86mmol) in N-methylpyrrolidone (20mL), add methylaminoacetaldehyde dimethyl acetal (9.37g, 78.65mmol ), methanesulfonic acid (1 mL) and anhydrous magnesium sulfate (5.68 g, 47.16 mmol), and then the reaction solution was heated to 110 ° C for 1 hour. Subsequently, the temperature of the reaction solution was raised to 150° C. for 2 hours.
  • Step 2 Dissolve LRQ-06-56 in toluene (10 mL) and cool down to 0°C, add NaH (368 mg, 9.20 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.41 g, 9.20 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • Step 3 LRQ-06-57 (400mg, 1.69mmol) was dissolved in THF (20mL), the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (5mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-58, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C11H17N2O2 + [M+H]+: 209.1285 , found : 209.1287.
  • Step 4 Dissolve LRQ-06-58 in DCM (10 mL) and cool down to 0°C, add carbon tetrabromide (841 mg, 2.54 mmol) and triphenylphosphine (887 mg, 3.38 mmol) in sequence, and react overnight at room temperature.
  • Example 42 Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1-methyl -5,6,7,8-Tetrahydropyrazolo[4,3-c]azepine Preparation of -4(1H)-ketone (I-A42) (IHCH-5207)
  • Step 1 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one (1.00g, 6.66mmol), sodium acetate (1.05g, 4.20mmol), and hydroxylamine hydrochloride ( 0.21g, 0.25mmol) was dissolved in absolute ethanol (16mL), and the reaction solution was heated to 60°C for overnight reaction. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain a white solid LRQ-06-47-1, which was directly put into the next reaction without purification.
  • HRMS ( ESI ) calcd for C8H12N3O + [M+H]+: 166.0975, found : 166.0977.
  • Step 2 LRQ-06-47-1 and triethylamine (2.02g, 19.98mmol) were dissolved in DCM (20mL), after p-toluenesulfonyl chloride (1.46g, 7.66mmol) was added, the reaction was refluxed for 0.5 hours. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a yellow solid, which was dissolved in three Fluoroacetic acid (5 mL) was refluxed for 0.5 hours.
  • Step 3 Dissolve LRQ-04-47 in toluene (10 mL) and cool down to 0°C, add NaH (311 mg, 7.79 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.19 g, 7.79 mmol) was added, and the reaction was refluxed overnight.
  • Step 4 LRQ-06-50 (600mg, 2.53mmol) was dissolved in THF (5mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-53, directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C10H16N3O2 + [ M +H]+: 210.1237 , found: 210.1242.
  • Step 5 Dissolve LRQ-06-53 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.26g, 3.79mmol) and triphenylphosphine (1.33g, 5.06mmol) in sequence, and react overnight at room temperature .
  • Example 43 Compound 2-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A43)(IHCH-5196)
  • Example 44 Compound 2-(3-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A44)(IHCH-5197)
  • Example 45 Compound 1-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4,4- Preparation of Dimethylpiperidine-2,6-dione(I-A45)(IHCH-5191)
  • Step 1 after dissolving 3,3-dimethylglutamine (1.00g, 7.08mmol) in DMF (10mL), add K 2 CO 3 (0.98g, 7.08mmol), 1,4-dibromobutane in sequence (4.59g, 21.25mmol), react overnight at room temperature. After the reaction was complete, add water (10 mL) to dilute solution, extracted with ethyl acetate (50mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Example 46 Compound 8-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-8-aza Preparation of spiro[4.5]decane-7,9-dione (I-A46)(IHCH-5192)
  • Step 1 after dissolving 3,3-tetramethylene glutarimide (1.00g, 5.98mmol) in DMF (10mL), add K 2 CO 3 (0.83g, 5.98mmol), 1,4- Dibromobutane (3.87g, 17.94mmol) was reacted overnight at room temperature.
  • Example 47 Compound 1-(2-(-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1,3-di Preparation of Hydrogen-2H-Benzo[d]imidazol-2-one(I-A47)(IHCH-5224)
  • Example 48 Compound 7-(4-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butoxy)quinone Preparation of Lin-2(1H)-one (I-B1)
  • Steps 1, 2, 3 The synthesis method of LRQ-04-165-Me is the same as the patent US 5631265A19970520, and LRQ-04-165-Me is a yellow solid (the yield of the three-step reaction is 17%).
  • HRMS(ESI) Calculated for C 12 H 15 N 2 O + [M+H] + : 203.1179 , measured value: 203.1185.
  • Step 4 After LRQ-04-165-Me (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2( 1H)-ketone (218mg, 0.74mmol), react overnight at 100°C.
  • Steps 1, 2, and 3 LRQ-04-165-Et uses 2-ethoxyphenylhydrazine as a raw material.
  • the synthesis method is the same as that of the patent US 5631265A19970520.
  • LRQ-04-165-Et is a yellow solid (the yield of the three-step reaction is 16 %).
  • Step 4 After LRQ-04-165-Et (105 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy) quinoline-2 ( 1H)-ketone (218mg, 0.74mmol), react overnight at 100°C.
  • Example 50 Compound 7-(3-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)quinone Preparation of Lin-2(1H)-one (I-B3)
  • Example 51 Compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)quinone Preparation of Lin-2(1H)-one (I-B4)
  • Example 52 Compound 7-(3-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)- Preparation of 3,4-dihydroquinolin-2(1H)-one (I-B5)
  • Example 53 Compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)- Preparation of 3,4-dihydroquinolin-2(1H)-one (I-B6)
  • Example 54 Compound 3-(trans-4-(2-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl ) ethyl) cyclohexyl) -1, the preparation of 1-dimethylurea (I-B7)
  • Example 55 Compound 3-(trans-4-(2-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl ) ethyl) cyclohexyl) -1, the preparation of 1-dimethylurea (I-B8)
  • Example 56 Compound 1-((8-Methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)methyl)cyclohexane Preparation of -1-alcohol (I-B9) (IHCH-5229)
  • Example 57 Compound 3-(3-(2-(8-methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)ethan base) cyclobutyl) -1,1-dimethylurea (I-B10) (IHCH-5226) preparation
  • Example 58 Compound 3-(3-(2-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)ethan base) cyclobutyl) -1,1-dimethylurea (I-B11) (IHCH-5227) preparation
  • Example 59 Compound 7-(4-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)quinoline-2 Preparation of (1H)-ketone (I-C1)
  • Step 1-3 The synthesis method of LRQ-05-03 is the same as the patent WO2004099212A1, and LRQ-05-03 is a reddish-brown solid (the yield of the three-step reaction is 57%).
  • Step 4 After dissolving LRQ-05-03 (99mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C.
  • Example 60 Compound 7-(4-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)-3,4 -Dihydroquinoline-2(1H)- Preparation of Ketones (I-C2)
  • Example 61 Compound 7-(3-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)propoxy)quinoline-2 Preparation of (1H)-ketone (I-C3)
  • Example 62 Compound 7-(3-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)propoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-C4)
  • Example 63 Compound (E)-7-((4-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)butan-2 Preparation of -en-1-yl)oxy)quinolin-2(1H)-one (I-C5)
  • Example 64 Compound (E)-7-((4-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)butan-2 Preparation of -en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (I-C6)
  • Example 65 Compound 3-(trans-4-(2-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)ethyl) )cyclohexyl)-1,1-dimethylurea (I-C7) preparation
  • Example 66 The compound N-(2-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)ethyl)tetrahydro-2H- Preparation of pyran-4-carboxamide (I-C8)
  • Step 1 After dissolving LRQ-05-03 (920mg, 4.55mmol) and DIPEA (3.53g, 27.30mmol) in DMF (10mL), add N-Boc-2-bromoethylamine (561mg, 2.51mmol), React overnight at 100°C.
  • Step 2 Dissolve LRQ-05-113 (70mg, 0.20mmol) in DCM (10mL), cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol), react overnight at room temperature.
  • Example 67 Compound 4,4-Difluoro-N-(2-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)B base) preparation of cyclohexane-1-carboxamide (I-C9)
  • LRQ-05-116 (70mg, 0.20mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol), react overnight at room temperature.
  • Example 68 Compound 7-(4-(9-ethoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)quinoline-2 Preparation of (1H)-ketone (I-C10)
  • Step 1 Dissolve 4-methoxyindole-2-carboxylic acid (5.0g, 26.15mmol) in dichloromethane (50mL), replace with nitrogen three times and cool the reaction solution to -78°C, add BBr 3 (39.2 mL, 2.0M dichloromethane solution). Then the reaction solution was warmed up to room temperature and reacted for 6 hours. After completion of the reaction, cool down to -30°C and add methanol (5 mL) to quench the reaction, then stir at room temperature for 1 hour, add water (30 mL) to dilute, extract with ethyl acetate (50 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate.
  • dichloromethane 50mL
  • Step 2 After LRQ-05-122 and K 2 CO 3 (3.6g, 26.15mmol) were dissolved in DMF (50mL), ethyl iodide (4.49g, 28.76mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain an orange-red oily liquid LRQ-05-123, which was directly purified without purification. into the next reaction.
  • HRMS (ESI) calcd for C13H16NO3 + [M+H] + : 234.1125 , found : 234.1121.
  • Step 3 Dissolve LRQ-05-123, potassium tert-butoxide (6.27g, 52.30mmol) in DMF (50mL), react at room temperature for 40 minutes, add bromoacetonitrile (4.40g, 39.23mmol), then heat up to 60°C React for 30 minutes. Then the reaction solution was cooled to room temperature and reacted overnight.
  • Step 4 After dissolving LRQ-05-124 (0.96g, 3.53mmol) in tetrahydrofuran (10mL), add lithium aluminum hydride (536mg, 14.1mmol), and react under reflux for 4 hours. After completion of the reaction, cool down to 0°C and add saturated ammonium chloride aqueous solution (5mL) to quench the reaction, then stir at room temperature for 1 hour, add water (30mL) to dilute, extract with ethyl acetate (50mL*3), wash with saturated brine, anhydrous sodium sulfate After drying, the solvent was distilled off under reduced pressure to obtain an orange-yellow solid LRQ-05-145, which was directly put into the next reaction without purification.
  • HRMS (ESI) calcd for C13H17N2O + [M+H] + : 217.1335 , found : 217.1329.
  • Step 5 After dissolving LRQ-05-145 (15mg, 0.07mmol) in DMF (8mL), add DIPEA (54mg, 0.42mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (31mg, 0.11mmol), react overnight at 100°C.
  • Example 69 Compound 3-(trans-4-(2-(9-ethoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)ethyl) ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-C11)
  • Example 70 Compound 1-((9-methoxy-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)cyclohexane-1- Preparation of alcohol (I-C12) (IHCH-5231)
  • Example 71 Compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)butyl Preparation of oxy)quinolin-2(1H)-one (I-D1)
  • LRQ-05-36 uses 2-nitro-3-fluoroanisole as a raw material, and the synthesis method is the same as the document European Journal of Medicinal Chemistry 186(2020) 111881, LRQ -05-03 is a reddish-brown solid (6-step reaction yield 20%).
  • Step 7 After dissolving LRQ-05-36 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C.
  • Example 72 Compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)butyl Preparation of oxy)-3,4-dihydroquinolin-2(1H)-one (I-D2)
  • Example 73 Compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)propane Preparation of oxy)quinolin-2(1H)-one (I-D3)
  • Example 74 Compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)propane Preparation of oxy)-3,4-dihydroquinolin-2(1H)-one (I-D4)
  • Example 75 Compound (E)-7-((4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H )-yl)but-2-en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (I-D5) preparation
  • Example 76 Compound 3-(trans-4-(2-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H )-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-D6) preparation
  • Example 77 Compound 1-((9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)methyl) Preparation of Cyclohexane-1-ol (I-D7) (IHCH-5230)
  • the affinity of the compound of the present invention for the dopamine D2 receptor is determined by the method of radioligand competition experiment.
  • cell membrane fractions containing specific dopamine D2 receptors are prepared.
  • a 10 cm culture dish was transfected with 10 ng dopamine D 2 receptor and 40 ⁇ L PEI. After 48 hours, the 10 cm culture dish was taken out from the cell room, in which the cultured cells had expressed dopamine D 2 receptor.
  • Use a vacuum pump to suck off the culture medium, add 3mL of lysate to each well, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant.
  • the cell pellet was transferred to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing dopamine D2 receptors.
  • ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing dopamine D2 receptors.
  • standard binding buffer was added to the cell membrane fraction containing dopamine D2 receptor, and the cell membrane was broken and resuspended with an electric tissue homogenizer.
  • 30 ⁇ L of different drugs were added to the 96-well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment.
  • the machine reading value reflects the situation on the intracellular ⁇ -arrestin2 membrane and the dissociation of the G protein trimer.
  • the former indicates the activation degree of the ⁇ -arrestin2 signaling pathway downstream of the dopamine D 2 receptor, and the latter indicates the G protein signaling pathway downstream of the dopamine D 2 receptor.
  • the degree of activation, and thus the agonistic effect of various compounds on the dopamine D2 receptor can be revealed. The results are shown in Table 2.
  • Biological test example 3 Affinity test of the compound of general formula (I) for 5-hydroxytryptamine 1A (5-HT 1A ) receptor
  • the affinity of the compound of the present invention for 5-hydroxytryptamine 1A (5-HT 1A ) receptor is determined by radioligand competition experiment method.
  • cell membrane fractions containing specific serotonin 1A receptors are prepared.
  • the 10cm culture dish covered with HEK-293T cells was transfected with 10 ⁇ g serotonin 1A receptor and 40 ⁇ L PEI. After 48 hours, the 10cm culture dish was taken out from the incubator, in which the cultured cells had expressed serotonin 1A receptor. Suck off the medium with a vacuum pump, add 3mL of lysate to each dish, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant.
  • the cell pellet was transferred to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing the serotonin 1A receptor.
  • the ligand-receptor binding experiment was performed on the 293T membrane fraction transiently expressing the serotonin 1A receptor.
  • 30 ⁇ L of different drugs were added to the 96-well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment.
  • Biological test example 4 Functional activity test of compounds for 5-hydroxytryptamine 1A (5-HT 1A ) receptors
  • 1 ⁇ g serotonin 1A receptor In order to detect the downstream G protein signaling pathway mediated by serotonin 1A receptor, on the first day, 1 ⁇ g serotonin 1A receptor, 1 ⁇ g G ⁇ i1 containing C-terminal algae luciferase ( G ⁇ i1 -Rluc), 1 ⁇ g G ⁇ 3 , 1 ⁇ g G ⁇ 9 containing C-terminal green fluorescent protein (G ⁇ 9 -GFP), and 16 ⁇ L PEI were used for transfection.
  • the EC50 is the concentration of the compound that gives the half maximal response in the experiment.
  • 2 Brackets E max % represent the percentage of the maximum response intensity (E max ) produced by the compound in the experiment relative to the endogenous ligand 5-hydroxytryptamine.
  • the affinity of the compound of the present invention for the 5-HT 2A receptor is determined by the method of radioligand competition experiment.
  • cell membrane fractions containing specific 5-HT 2A receptors are prepared.
  • a 10cm culture dish was transfected with 10ng 5-HT 2A receptor and 40 ⁇ L PEI. After 48 hours, the 10cm culture dish was taken out from the cell room, in which the cultured cells had expressed the 5-HT 2A receptor.
  • the cells After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing the 5-HT 2A receptor. In the second step, ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing 5-HT 2A receptors.
  • the compound of the present invention has very weak affinity to 5-HT 2A receptors, and has selectivity for D2 receptors and 5-HT 1A receptors relative to 5-HT 2A receptors.
  • the results in Table 5 show that compounds I-A1, I-A2, I-A16, I-A20, I-A21, I-A28, I-A29 and I-B7 have very weak affinity to the 5-HT 2A receptor. Comparing the data in Table 1, it can be seen that the compounds of the present invention have good selectivity for D2 receptors relative to 5-HT 2A receptors.
  • Intravenous administration administration dose 3mg/kg, administration concentration is 0.6mL/kg
  • intragastric administration administration dose 10mg/kg, administration concentration is 1mL/kg
  • all with 5%DMSO+5% Solutol+90% normal saline is the vehicle.
  • Sample collection 0.10mL blood is taken from each animal through the orbit each time, anticoagulated with EDTAK 2 , and the collection time point is IV/PO group: 5, 15, 30min, 1, 2, 4, 6, 8, after administration of the test substance 24h.
  • the blood samples were placed on ice after collection, and the plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). Store at –80°C until analysis.
  • the data acquisition and control system software is Analyst1.5.1 software (Applied Biosystem).
  • the peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as the index, and the concentration of the sample is used for regression.
  • Regression method linear regression, the weight coefficient is 1/X 2 .
  • Pharmacokinetic parameters were analyzed with WinNonlin Professional v6.3 (Pharsight, USA) using non-compartmental models.
  • C max is the measured maximum blood drug concentration
  • the area under the blood drug concentration-time curve AUC (0 ⁇ t) is calculated by the trapezoidal method
  • t max is the peak time of blood drug concentration after administration.
  • the SD rat metabolic properties of the compounds of the present invention are shown in Table 6-8. It can be seen from the data listed in Tables 6-8 that the compounds of the present invention have good pharmacokinetic properties, reasonable half-life and good oral bioavailability in SD rats.
  • the drug concentrations in plasma and brain tissue were analyzed and compared by LC/MS/MS.
  • the drug concentrations and ratios of the compounds in plasma and brain tissue are shown in Table 9. It can be seen from Table 9 that the compounds of the present invention have good brain-penetrating properties.
  • This model uses C57B6 mice as experimental animals, through acute injection of NMDA antagonist MK801, to induce the behavioral characterization of hyperkinesia in the open field environment, and to test the effect of different compounds on the hyperkinesia phenotype induced by MK801 inhibitory effect. All mouse behavior experiments were carried out during the light period of the mice, and the experiment was recorded through the camera and automatically tracked and counted by the behavioral tracking software. The compound was given by intraperitoneal injection After the injection was completed, the mice immediately entered the empty field and began to record the movement trajectory.
  • mice received 0.2mg/kg of MK801 by intraperitoneal injection, and returned to the empty field immediately after the administration to continue recording 120 minutes. motion track.
  • the accumulative moving distance of the mice was counted as a data sampling point every five minutes. Data statistics are carried out using Student-t-test, p ⁇ 0.05 is *, p ⁇ 0.01 is **, p ⁇ 0.001 is ***, p ⁇ 0.0001 is ****. See Table 10 for the total moving distance of mice within 0-45 minutes under the combined action of different doses of the compound of the present invention and MK801 (0.2 mg/kg).
  • test results of open field exercise ability shown in Table 10 show that the compounds I-A1, I-A12 and I-B7 of the present invention can significantly inhibit the high spontaneous activity of mice induced by MK801 at different doses.

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Abstract

Disclosed are a tricyclic compound, and a preparation method therefor and the use thereof. The tricyclic compound has a structure as shown in formula I, and can be used for treating various mental diseases and neurodegenerative diseases such as schizophrenia, depression and Parkinson's disease.

Description

三并环类化合物、其制备方法和用途Tricyclic compound, its preparation method and use
本申请要求申请日为2022年1月29日的中国专利申请202210112894.8的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 202210112894.8 with the filing date of January 29, 2022. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明涉及一种三并环类化合物、其制备方法和用途。The present invention relates to a tricyclic compound, its preparation method and application.
背景技术Background technique
单胺类G蛋白偶联受体(GPCR)，例如多巴胺受体、5-羟色胺(5-HT)受体等，与多种精神疾病和神经退行性疾病相关，如精神分裂症、抑郁症、帕金森氏症等。相应地，大多数抗精神疾病和缓解神经退行性疾病的药物通过调节多巴胺受体、5-羟色胺受体等单胺类GPCR的功能发挥药效。Monoamine G protein-coupled receptors (GPCRs), such as dopamine receptors, 5-hydroxytryptamine (5-HT) receptors, etc., are associated with a variety of psychiatric and neurodegenerative diseases, such as schizophrenia, depression, Parkinson's disease, etc. Correspondingly, most drugs for antipsychotic and neurodegenerative diseases exert their medicinal effects by regulating the functions of monoamine GPCRs such as dopamine receptors and serotonin receptors.
多巴胺受体有五种亚型(D1-5)，其中D1、D5为D1类受体，主要与Gs蛋白偶联，激活后升高细胞内环磷酸腺苷(cAMP)水平；D2、D3、D4为D2类受体，主要与Gi蛋白偶联，激活后降低细胞内cAMP水平。多巴胺能信号通路的异常与精神分裂症、帕金森氏症等多种疾病相关。靶向多巴胺D2受体的小分子拮抗剂或部分激动剂是有效的抗精神分裂药物，如氟哌啶醇、奥氮平、利培酮、阿立哌唑(aripiprazole)、卡利拉嗪(cariprazine)等的主要作用靶点均为多巴胺D2受体。与D2同一个亚家族的多巴胺D3受体也是很多抗精神分裂药物的重要靶点(如卡利拉嗪)，高选择性的D3受体拮抗剂或部分激动剂同时还具有治疗药物成瘾的潜力。There are five subtypes of dopamine receptors (D1-5), among which D 1 and D 5 are D 1 type receptors, which are mainly coupled with G s protein, and increase the level of intracellular cyclic adenosine monophosphate (cAMP) after activation; D 2 , D 3 , and D 4 are D 2 receptors, which are mainly coupled with G i protein, and reduce intracellular cAMP level after activation. Abnormalities in the dopaminergic signaling pathway are associated with many diseases such as schizophrenia and Parkinson's disease. Small molecule antagonists or partial agonists targeting dopamine D2 receptors are effective antischizophrenic drugs, such as haloperidol, olanzapine, risperidone, aripiprazole, cariprazine (cariprazine) and other main targets are dopamine D2 receptors. The dopamine D3 receptor of the same subfamily as D2 is also an important target of many antischizophrenic drugs (such as cariprazine), and highly selective D3 receptor antagonists or partial agonists also have therapeutic drugs Addictive Potential.
多巴胺受体的五种亚型中，对于D2受体的研究最为广泛和深入。根据多巴胺D2受体配体的内在活性的不同，可将其分为激动剂、拮抗剂或部分激动剂等多种形式。临床在用药物如普拉克索(Pramipexole)、罗匹尼罗(Ropinirole)、罗替戈汀(Rotigotine)等，为多巴胺D2受体的激动剂，通过激活多巴胺D2受体发挥治疗作用，用于帕金森氏症和多动腿综合征等疾病的治疗。非经典抗精神分裂症药物如氟哌啶醇、奥氮平、利培酮等为多巴胺D2受体拮抗剂，通过拮抗D2受体发挥药效。而最新一代的抗精神分裂症药物，即阿立哌唑(aripiprazole)、依匹哌唑(brexpiprazole)和卡利拉嗪(cariprazine)，则为多巴胺D2受体的部分激动剂，能够发挥稳定多巴胺能信号的作用，也被称为多巴胺稳定剂。Among the five subtypes of dopamine receptors, D2 receptors are the most widely and deeply studied. According to the intrinsic activity of dopamine D2 receptor ligands, it can be divided into various forms such as agonists, antagonists or partial agonists. Clinically used drugs such as Pramipexole (Pramipexole), Ropinirole (Ropinirole), and Rotigotine (Rotigotine) are agonists of dopamine D2 receptors, which play a therapeutic role by activating dopamine D2 receptors. Treatment of disorders such as Parkinson's disease and restless legs syndrome. Non-classic antischizophrenia drugs such as haloperidol, olanzapine, risperidone, etc. are dopamine D2 receptor antagonists, which exert their drug effects by antagonizing D2 receptors. The latest generation of antischizophrenia drugs, aripiprazole, brexpiprazole, and cariprazine, are partial agonists of dopamine D2 receptors, which can stabilize The role of dopaminergic signaling, also known as dopamine stabilizers.
值得一提的是，目前已知的绝大多数多巴胺D2拮抗剂和部分激动剂，均存在选择性差的缺点。对于靶向多巴胺D2受体的药物，化合物对于其他靶标的作用会影响药物的药效和毒副作用。例如，对于多巴胺D2受体的拮抗剂，药物对于5-HT2A受体的拮抗作用能够改善化合物的锥体外系副作用，在这种情况下增加5-HT2A受体的拮抗作用是有益的。实际上，5-HT2A也是抗精神分裂症药物的另一个重要靶标，是多靶点的“非典型”抗精神分裂症药物的一个主要作用靶点，抗精神分裂症药物对于5-HT2A受体和多巴胺D2受体的亲和力相对强弱是区分“典型”与“非典型”药物的重要依据。但对于很多其他靶标的作用，例如对于组胺H1的拮抗作用，对于5-HT2C受体的拮抗作用，以及药物对于胆碱受 体、肾上腺素受体的脱靶作用，则是目前大多数抗精神分裂症药物具有很多毒副作用的原因，例如引起体重增加、诱发糖尿病等。部分药物对于胆碱能活性的脱靶抑制作用，也是导致患者认知功能进一步恶化的可能原因。It is worth mentioning that most of the currently known dopamine D2 antagonists and partial agonists have the disadvantage of poor selectivity. For drugs targeting dopamine D2 receptors, the effect of the compound on other targets will affect the efficacy and side effects of the drug. For example, for antagonists of dopamine D2 receptors, drug antagonism of 5- HT2A receptors can improve the extrapyramidal side effects of the compound, in which case increased 5- HT2A receptor antagonism is beneficial . In fact, 5-HT 2A is also another important target of anti-schizophrenia drugs, and it is a main target of multi-target "atypical" anti-schizophrenia drugs . The relative affinity of receptors and dopamine D2 receptors is an important basis for distinguishing "typical" and "atypical" drugs. But for many other targets, such as histamine H 1 antagonism, 5-HT 2C receptor antagonism, and drug effects on choline receptors The off-target effect of the body and adrenergic receptors is the reason why most anti-schizophrenia drugs have many side effects, such as causing weight gain and inducing diabetes. The off-target inhibitory effect of some drugs on cholinergic activity is also a possible reason for the further deterioration of cognitive function in patients.
最近的研究证明，5-HT2A受体的拮抗作用对于多巴胺D2受体部分激动剂的抗精神分裂症活性不是必须的，降低5-HT2A受体拮抗作用的D2受体部分激动剂具有更好的改善精神分裂症阴性症状和认知功能的药效(Chen等，Nat Neurosci 2022，25，39–49)。Recent studies have demonstrated that 5-HT 2A receptor antagonism is not necessary for the antischizophrenia activity of dopamine D2 receptor partial agonists, and D2 receptor partial agonists that reduce 5-HT 2A receptor antagonism have more Good drug efficacy for improving negative symptoms and cognitive function in schizophrenia (Chen et al., Nat Neurosci 2022, 25, 39–49).
另一个与精神分裂症等精神疾病治疗密切相关的靶点是血清素5-HT1A受体。5-HT1A受体激动剂在治疗抑郁症、焦虑症，改善精神分裂症患者的阴性症状及认知功能等方面表现出良好的临床应用前景。对于多巴胺D2受体的拮抗剂，药物对于5-HT1A受体的激动或部分激动作用也能够改善药物的锥体外系副作用。非典型抗精神分裂症药物如阿立哌唑、依匹哌唑和卡利拉嗪等均具有5-HT1A受体的部分激动剂作用。用于治疗广泛性焦虑状态的坦度螺酮(Tandospirone)、具有抗抑郁和抗焦虑作用的吉哌隆(Gepirone)、治疗焦虑症相关症状的丁螺环酮(Buspirone)、具有抗抑郁和抗焦虑作用的Ipsapirone等，都具有5-HT1A受体激动剂的药理作用。5-HT1A受体激动剂Flibanserin于2015年被美国FDA批准用于治疗妇女性欲低下。5-HT1A受体激动剂或部分激动剂是新型抗精神分裂症、抗抑郁症、抗焦虑症等新药开发的重要方向。Another target closely related to the treatment of psychiatric disorders such as schizophrenia is the serotonin 5-HT 1A receptor. 5-HT 1A receptor agonists have shown good clinical application prospects in the treatment of depression, anxiety, and improvement of negative symptoms and cognitive functions in patients with schizophrenia. For dopamine D2 receptor antagonists, the agonistic or partial agonistic effect of the drug on the 5-HT 1A receptor can also improve the extrapyramidal side effects of the drug. Atypical antischizophrenia drugs such as aripiprazole, ebiprazole, and cariprazine all have partial agonist effects on 5-HT 1A receptors. Tandospirone for generalized anxiety state, Gepirone for antidepressant and anxiolytic effects, Buspirone for anxiety-related symptoms, antidepressant and anti-anxiety Ipsapirone, which has anxiolytic effect, has the pharmacological effect of 5-HT 1A receptor agonist. The 5-HT 1A receptor agonist Flibanserin was approved by the US FDA in 2015 for the treatment of low libido in women. 5-HT 1A receptor agonist or partial agonist is an important direction for the development of new anti-schizophrenia, anti-depression, anti-anxiety and other new drugs.
因此，针对多巴胺D2受体、5-HT1A受体等单胺类GPCR开发具有新的功能特征和选择性的小分子化合物，具有获得新型抗精神疾病药物，以增强药效、减少相关毒副作用的潜力。Therefore, the development of small molecular compounds with new functional characteristics and selectivity for monoamine GPCRs such as dopamine D 2 receptors and 5-HT 1A receptors has the potential to obtain new antipsychotic drugs to enhance drug efficacy and reduce related toxicity. Potential for side effects.
发明内容Contents of the invention
为克服现有技术中的上述问题，本发明提供了一种三并环类化合物、其制备方法和用途。本发明的化合物能够用于治疗如精神分裂症、抑郁症、帕金森氏症等多种精神疾病和神经退行性疾病。In order to overcome the above-mentioned problems in the prior art, the present invention provides a tricyclic compound, its preparation method and application. The compound of the present invention can be used to treat various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease and the like.
本发明提供了一种式I所示的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，
The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer or solvate thereof,
其中，in,
X为N、O、NRa或CRb；X is N, O, NR a or CR b ;
Y为C或N；Y is C or N;
为双键或者单键； is a double bond or a single bond;
Ra和Rb各自独立地为H或C1-C6烷基；R a and R b are each independently H or C 1 -C 6 alkyl;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
Rc和Rd各自独立地为H或C1-C6烷基； R c and R d are each independently H or C 1 -C 6 alkyl;
m、n1和n2各自独立地为1、2、3、4、5或6；m, n1 and n2 are each independently 1, 2, 3, 4, 5 or 6;
M为不存在、-O-或-NH-C(O)-；M is absent, -O- or -NH-C(O)-;
环Q为饱和或部分不饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；Ring Q is a saturated or partially unsaturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or an 8-11 membered Bicyclocyclic rings; one ring in the 8-11 membered bicyclocyclic rings is a saturated or partially unsaturated 5-7-membered carbocycle, or a saturated or partially unsaturated 5-7-membered heterocyclic ring, and the other One ring is a benzene ring or a 5-6 membered heteroaromatic ring;
R1为C1-C6烷基或卤代C1-C6烷基；R 1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
R2各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基或卤代C1-C6烷氧基；R 2 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl or halogenated C 1 -C 6 alkoxy;
R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、-NH-C(O)Re或-NH-S(O)2Re；R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkoxy, -NH-C(O)R e or -NH-S(O) 2 R e ;
或者，两个R3与其相连的原子形成3-8元的环烷基；Alternatively, two R 3 form a 3-8 membered cycloalkyl group with the atoms connected to them;
Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
R4为氧代(＝O)； R is oxo (=O);
p、q和r各自独立地为0、1、2、3或4；p, q and r are each independently 0, 1, 2, 3 or 4;
所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S。The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is 1, 2 or 3 each independently, and each of the heteroatoms is N, O or S independently.
在一些实施方案中，Ra和Rb为H。In some embodiments, Ra and Rb are H.
在一些实施方案中，Rc和Rd为H。In some embodiments, Rc and Rd are H.
在一些实施方案中，m为2、3或4。In some embodiments, m is 2, 3 or 4.
在一些实施方案中，m为1。In some embodiments, m is 1.
在一些实施方案中，n1和n2为1。In some embodiments, n1 and n2 are 1.
在一些实施方案中，L为-(CH2)2-、-(CH2)3-、-(CH2)4-或-(CH2)-CH＝CH-(CH2)-。In some embodiments, L is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, or -(CH 2 )-CH=CH-(CH 2 )-.
在一些实施方案中，L为-(CH2)-。In some embodiments, L is -( CH2 )-.
在一些实施方案中，M中，-NH-C(O)-通过N原子与L相连。In some embodiments, in M, -NH-C(O)- is attached to L through the N atom.
在一些实施方案中，R1各自独立地为C1-C6烷基，例如甲基、乙基或异丙基。In some embodiments, each R 1 is independently C 1 -C 6 alkyl, such as methyl, ethyl, or isopropyl.
在一些实施方案中，R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；较佳地，R3各自独立地为C1-C6烷基或-NH-C(O)Re。In some embodiments, each R 3 is independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; Preferably, each of R 3 is independently C 1 -C 6 alkyl or -NH-C(O)R e .
在一些实施方案中，p为0。In some embodiments, p is 0.
在一些实施方案中，环Q通过C原子与M相连。In some embodiments, ring Q is linked to M through a C atom.
在一些实施方案中，环Q中，所述3-8元的碳环为4、5、6或7元的碳环。In some embodiments, in the ring Q, the 3-8 membered carbocycle is a 4, 5, 6 or 7 membered carbocycle.
在一些实施方案中，环Q中，所述3-8元的杂环为6元的杂环。In some embodiments, in the ring Q, the 3-8 membered heterocycle is a 6-membered heterocycle.
在一些实施方案中，环Q中，所述3-8元的杂环中的杂原子为N或O，例如N原子。In some embodiments, in the ring Q, the heteroatom in the 3-8 membered heterocyclic ring is N or O, such as N atom.
在一些实施方案中，环Q中，所述6-10元的芳环为苯环。 In some embodiments, in the ring Q, the 6-10 membered aromatic ring is a benzene ring.
在一些实施方案中，环Q中，所述5-10元杂芳环中的杂原子个数1或2个。In some embodiments, in ring Q, the number of heteroatoms in the 5-10 membered heteroaromatic ring is 1 or 2.
在一些实施方案中，环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环，其中所述5-7元的杂环和5-6元的杂芳环中的杂原子的个数各自独立地为1或2个，杂原子为N。In some embodiments, in the ring Q, one ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heterocycle. A heteroaryl ring, wherein the number of heteroatoms in the 5-7 membered heterocyclic ring and the 5-6 membered heteroaryl ring is independently 1 or 2, and the heteroatom is N.
在一些实施方案中，环Q为(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、 (例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)、(例如)或(例如)。In some embodiments, Ring Q is (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，q为0、1或2。In some embodiments, q is 0, 1 or 2.
在一些实施方案中，r为0、1或2。In some embodiments, r is 0, 1 or 2.
在一些实施方案中，为 其中，R3-1为R3，R3-2为H或R3，q和R3的定义如本发明任一方案所述。In some embodiments, for Wherein, R 3-1 is R 3 , R 3-2 is H or R 3 , and the definitions of q and R 3 are as described in any scheme of the present invention.
在一些实施方案中，中，R3-1各自独立地为-NH-C(O)Re或-NH-S(O)2Re。In some embodiments, In, each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R e .
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，中，R3-1为羟基。In some embodiments, In, R 3-1 is hydroxyl.
在一些实施方案中，为例如在一些实施方案中，中，R3-1各自独立地为-NH-C(O)Re或-NH-S(O)2R。In some embodiments, for For example In some embodiments, In, each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R.
在一些实施方案中，中，R3-1各自独立地为-NH-C(O)Re或-NH-S(O)2Re。In some embodiments, In, each R 3-1 is independently -NH-C(O)R e or -NH-S(O) 2 R e .
在一些实施方案中，R3-1各自独立地为F、Cl、Br、I、羟基、C1-C6烷基或C1-C6烷氧基。In some embodiments, each R 3-1 is independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，为 In some embodiments, for
在一些实施方案中，为以下任一方案：In some embodiments, for any of the following options:
方案(1)：为 plan 1): for
方案(2)：为 Scenario 2): for
方案(3)：为 Scheme (3): for
方案(4)：为 Scheme (4): for
方案(5)：为 Scheme (5): for
方案(6)：为 Scheme (6): for
在一些实施方案中，L为-(CRcRd)-，M为不存在。In some embodiments , L is -( CRcRd )- and M is absent.
在一些实施方案中，L为-(CRcRd)2-，M为不存在或-NH-C(O)-。In some embodiments, L is -( CRcRd ) 2- , M is absent or -NH-C(O)-.
在一些实施方案中，L为-(CRcRd)3-，M为-O-。 In some embodiments, L is -(CR c Rd ) 3 - and M is -O-.
在一些实施方案中，L为-(CRcRd)3-，M为不存在。In some embodiments, L is -( CRcRd ) 3- and M is absent .
在一些实施方案中，L为-(CRcRd)4-，M为-O-。In some embodiments, L is -(CR c R d ) 4 - and M is -O-.
在一些实施方案中，L为-(CRcRd)4-，M为不存在。In some embodiments, L is -( CRcRd ) 4- and M is absent .
在一些实施方案中，L为-(CRcRd)-CH＝CH-(CRcRd)-，M为-O-。In some embodiments , L is -( CRcRd )-CH=CH-( CRcRd )- and M is -O- .
在一些实施方案中，环Q中，所述3-8元的碳环为5-8元的碳环，优选为5-7元碳环，例如6-7元碳环。In some embodiments, in the ring Q, the 3-8 membered carbocycle is a 5-8 membered carbocycle, preferably a 5-7 membered carbocycle, such as a 6-7 membered carbocycle.
在一些实施方案中，环Q中，所述3-8元的杂环为含氮6元杂环，例如六氢吡啶；In some embodiments, in the ring Q, the 3-8 membered heterocycle is a nitrogen-containing 6-membered heterocycle, such as hexahydropyridine;
在一些实施方案中，环Q中，所述5-10元杂芳环为 In some embodiments, in ring Q, the 5-10 membered heteroaromatic ring is
在一些实施方案中，环Q中，所述8-11元的双环并环为8-10元的双环并环。In some embodiments, in ring Q, the 8-11 membered bicyclo is an 8-10 membered bicyclo.
在一些实施方案中，环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环里的5-7元的杂环为5-6元杂环，例如6元杂环。In some embodiments, in the ring Q, the 5-7 membered heterocyclic ring in the 8-11 membered bicyclic ring is saturated or partially unsaturated, and the 5-7 membered heterocyclic ring is 5-6 A membered heterocycle, such as a 6-membered heterocycle.
在一些实施方案中，环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环里的5-7元的杂环至多含有一个N原子或至多含有一个氧原子。In some embodiments, in the ring Q, one ring in the 8-11 membered bicyclic ring is saturated or partially unsaturated, and the 5-7 membered heterocycle in the 5-7 membered heterocycle contains at most one N atoms or contain at most one oxygen atom.
在一些实施方案中，L为-(CRcRd)2-，环Q中，所述8-11元的双环并环中的饱和或部分不饱和的5-7元的杂环中至多含有一个N。In some embodiments, L is -(CR c R d ) 2 -, and in ring Q, the saturated or partially unsaturated 5-7 membered heterocyclic ring in the 8-11 membered bicyclic ring contains at most a N.
在一些实施方案中，L为-(CRcRd)4-，M为-O-，所述8-11元的双环并环中的苯环或5-6元的杂芳环为5-6元芳杂环。In some embodiments, L is -(CR c R d ) 4 -, M is -O-, and the benzene ring in the 8-11 membered bicyclic ring or the 5-6 membered heteroaryl ring is 5- 6-membered aromatic heterocycle.
在一些实施方案中，环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环。In some embodiments, ring Q is a saturated 3-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered heteroaryl ring, or an 8- 11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or a saturated or partially unsaturated 5-7-membered heterocyclic ring , and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.
在一些实施方案中，环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环。In some embodiments, Ring Q is a saturated 3-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, a 5-10 membered heteroaryl ring, or an 8-10 membered bicyclic and Ring; one ring in the 8-10 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is A benzene ring or a 5-6 membered heteroaromatic ring.
在一些实施方案中，所述式I所示的化合物具有如下任一结构：
In some embodiments, the compound represented by the formula I has any of the following structures:
其中，各变量的定义如本发明任一方案所述。 Wherein, the definition of each variable is as described in any scheme of the present invention.
在一些实施方案中，所述的化合物为以下任一方案：In some embodiments, the compound is any of the following:
方案(1)：plan 1):
X为N、O、NRa或CRb；X is N, O, NR a or CR b ;
Y为C或N；Y is C or N;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
Rc和Rd各自独立地为H； Rc and Rd are each independently H;
m为1、2、3或4；m is 1, 2, 3 or 4;
n1和n2为1；n1 and n2 are 1;
P为0；P is 0;
r为0、1或2；r is 0, 1 or 2;
q为0、1或2；q is 0, 1 or 2;
M为不存在、-O-或-NH-C(O)-；M is absent, -O- or -NH-C(O)-;
环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, a 6-10-membered aromatic ring, a 5-10-membered heteroaromatic ring or an 8-11-membered bicyclic ring ; One ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is benzene Ring or 5-6 membered heteroaromatic ring;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；较佳地，R3各自独立地为羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；或者，两个R3与其相连的原子形成3-8元的环烷基；R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; preferably, R 3 are each independently hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 are connected to the atom to form 3-8 Cycloalkyl;
Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
R4为氧代(＝O)； R is oxo (=O);
所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S。The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is 1, 2 or 3 each independently, and each of the heteroatoms is N, O or S independently.
方案(2)：Scenario 2):
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
Rc和Rd各自独立地为H； Rc and Rd are each independently H;
m为1、2、3或4；m is 1, 2, 3 or 4;
n1和n2为1；n1 and n2 are 1;
P为0；P is 0;
r为0、1或2；r is 0, 1 or 2;
q为0、1或2；q is 0, 1 or 2;
M为不存在、-O-或-NH-C(O)-；M is absent, -O- or -NH-C(O)-;
环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元 的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环；所述8-10元的双环并环中的饱和或部分不饱和的5-6元的杂环里的5-6元的杂环含一个氧原子、一个氮原子、两个氮原子、或、一个氧原子和一个氮原子；Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, phenyl, a 5-10-membered heteroaryl ring or an 8-10-membered Bicyclocyclic rings; one ring in the 8-10 membered bicyclocyclic rings is a saturated or partially unsaturated 5-7-membered carbocyclic ring, or a saturated or partially unsaturated 5-6-membered heterocyclic ring, and the other One ring is a benzene ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, two nitrogen atoms, or, an oxygen atom and a nitrogen atom;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
R3为羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；或者，两个R3与其相连的原子形成3-8元的环烷基；R 3 is hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 and the atoms connected to it form a 3-8 membered Cycloalkyl;
Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
R4为氧代(＝O)； R is oxo (=O);
所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
方案(3)：Scheme (3):
X为N或O；X is N or O;
Y为C；Y is C;
P为0；P is 0;
r为0、1或2；r is 0, 1 or 2;
q为0、1或2；q is 0, 1 or 2;
L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2、3或4；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
m为2时，M为不存在或-NH-C(O)-，环Q为饱和的5-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-7 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
m为3时，M为不存在；环Q为部分不饱和的3-8元的杂环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的杂环，另一个环为苯环；When m is 3, M does not exist; Ring Q is a partially unsaturated 3-8 membered heterocycle or 8-11 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-7 membered heterocyclic ring, the other ring is a benzene ring;
m为4时，M为-O-，环Q为8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的杂环，另一个环为5-6元的杂芳环；When m is 4, M is -O-, and ring Q is an 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
或m为4时，M为不存在；Or when m is 4, M does not exist;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
R3各自独立地为F、Cl、Br、I、C1-C6烷基或-NH-C(O)Re；较佳地，R3各自独立地为F、Cl、Br、I、C1-C6烷基或-NH-C(O)Re；或者，两个R3与其相连的原子形成3-8元的环烷基；Each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O) Re ; preferably, each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
R4为氧代(＝O)； R is oxo (=O);
所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立 地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently Ground is N, O or S;
所述8-11元的双环并环中的饱和或部分不饱和的5-7元的杂环里的5-7元的杂环含一个氧原子、一个氮原子、两个氧原子、或、一个氧原子和一个氮原子；The 5-7 membered heterocycle in the saturated or partially unsaturated 5-7 membered heterocycle in the 8-11 membered bicyclic ring contains one oxygen atom, one nitrogen atom, two oxygen atoms, or, an oxygen atom and a nitrogen atom;
方案(4)：Scheme (4):
X为N或O；X is N or O;
Y为C；Y is C;
P为0；P is 0;
r为0、1或2；r is 0, 1 or 2;
q为0、1或2；q is 0, 1 or 2;
L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2、3或4；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
m为2时，M为不存在或-NH-C(O)-，环Q为饱和的5-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环；When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-6 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
m为3时，M为不存在，环Q为部分不饱和的3-8元的杂环或8-10元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为苯环；When m is 3, M does not exist, ring Q is a partially unsaturated 3-8 membered heterocycle or 8-10 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-6 membered heterocyclic ring, the other ring is a benzene ring;
m为4时，M为-O-，环Q为8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为5-6元的杂芳环；When m is 4, M is -O-, and ring Q is an 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-6-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
或m为4时，M为不存在；环Q为饱和或部分不饱和的3-8元的杂环或8-10元的双环并环；所述8-6元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为苯环；Or when m is 4, M does not exist; the ring Q is a saturated or partially unsaturated 3-8 membered heterocycle or an 8-10 membered bicyclic ring; one of the 8-6 membered bicyclic rings The ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
R3各自独立地为C1-C6烷基、-NH-C(O)Re；或者，两个R3与其相连的原子形成3-8元的环烷基；Each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
R4为氧代(＝O)； R is oxo (=O);
所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
所述8-10元的双环并环中的饱和或部分不饱和的5-6元的杂环里的5-6元的杂环含一个氧原子、一个氮原子、或、一个氧原子和一个氮原子；The 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, or, an oxygen atom and an Nitrogen atom;
方案(5)：Scheme (5):
X为O；Y为C；P为0；X is O; Y is C; P is 0;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为1、2、3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 1, 2 , 3 or 4;
L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
L为-(CRcRd)m-，m为1时，M为不存在，环Q为饱和的6元碳环，R3为羟基； L is -(CR c R d ) m -, when m is 1, M does not exist, the ring Q is a saturated 6-membered carbon ring, and R 3 is a hydroxyl group;
L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的3-8元碳环、六氢吡啶、噻吩、苯基，R3各自独立地为C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 3-8 membered carbocycle, hexahydropyridine, thiophene, benzene group, each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e , and R e is a C 1 -C 6 alkyl group;
L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
L为-(CRcRd)m-，m为4时，M为-O-或不存在，环Q为六氢吡啶、 L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine,
环Q为六氢吡啶时，R3各自独立地为C1-C6烷基；When ring Q is hexahydropyridine, each R 3 is independently C 1 -C 6 alkyl;
环Q为时，q为0；Ring Q is When , q is 0;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
方案(6)：Scheme (6):
X为N；Y为C；P为0；X is N; Y is C; P is 0;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为2或3；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 2 or 3 ;
L为-(CRcRd)m-，m为2时，M为不存在，环Q为饱和的5-7元碳环，R3各自独立地为-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 5-7 membered carbon ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
L为-(CRcRd)m-，m为3时，M为-O-，环Q为q为0；L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
R1为甲基；R 1 is methyl;
方案(7)：Scheme (7):
X为C；Y为N；P为0；X is C; Y is N; P is 0;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 3 or 4 ;
L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
L为-(CRcRd)m-，m为4时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
方案(8)：Scheme (8):
X为O；Y为C；P为0；X is O; Y is C; P is 0;
L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2或4； L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 4;
L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的6-7元碳环、苯基、8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和的5-7元的杂环，另一个环为5-6元的杂芳环；所述5-6元的杂芳环含有一个或两个氮原子；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 6-7-membered carbocycle, phenyl, 8-11-membered Bicyclic rings; one ring in the 8-11-membered bicyclic rings is a saturated 5-7-membered heterocyclic ring, and the other ring is a 5-6-membered heteroaromatic ring; the 5-6-membered Heteroaromatic rings contain one or two nitrogen atoms;
L为-(CRcRd)m-，m为4时，M为不存在或-O-；L is -(CR c R d ) m -, when m is 4, M is absent or -O-;
L为-(CRcRd)m-，m为4，M为不存在时，环Q为部分不饱和的6元杂环或 L is -(CR c R d ) m -, m is 4, and when M is absent, ring Q is a partially unsaturated 6-membered heterocyclic ring or
环Q为部分不饱和的6元杂环时，所述部分不饱和的6元杂环中杂原子为氮原子，杂原子个数各自独立地为1、2或3个；When the ring Q is a partially unsaturated 6-membered heterocyclic ring, the heteroatom in the partially unsaturated 6-membered heterocyclic ring is a nitrogen atom, and the number of heteroatoms is 1, 2 or 3 independently;
L为-(CRcRd)m-，m为4，M为-O-时，环Q为部分不饱和的6元杂环或 When L is -(CR c R d ) m -, m is 4, and M is -O-, ring Q is a partially unsaturated 6-membered heterocyclic ring or
R3各自独立地为F、C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基。R 3 is each independently F, C 1 -C 6 alkyl, -NH-C(O)R e , and R e is C 1 -C 6 alkyl.
方案(9)：Scheme (9):
X为O；Y为C；P为0；X is O; Y is C; P is 0;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为2或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 2 or 4 ;
L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的4-6元碳环、噻吩、苯基，R3各自独立地为C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-6 membered carbocycle, thiophene, phenyl, R 3 Each is independently C 1 -C 6 alkyl, -NH-C(O)R e , Re is C 1 -C 6 alkyl;
L为-(CRcRd)m-，m为4时，M为-O-或不存在，环Q为六氢吡啶、 q为0；L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine, q is 0;
R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
方案(10)：Scheme (10):
X为N；Y为C；P为0；X is N; Y is C; P is 0;
L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2或3；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 3;
L为-(CRcRd)m-，m为2时，M为不存在，环Q为饱和的6元碳环，R3各自独立地为-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 6-membered carbocyclic ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
L为-(CRcRd)m-，m为3时，M为-O-，环Q为q为0；L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
R1为甲基；R 1 is methyl;
方案(11)： Scheme (11):
X为C；Y为N；P为0；X is C; Y is N; P is 0;
L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 3 or 4 ;
L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
L为-(CRcRd)m-，m为4时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
在一些实施方案中，所述式I所示的化合物具有如下任一结构：



In some embodiments, the compound represented by the formula I has any of the following structures:



本发明还提供一种式I所示化合物的制备方法，其包括如下步骤：在溶剂(例如N,N-二甲基甲酰胺和水的混合溶剂)中，将式II所示化合物与式III所示化合物(例如在DIPEA作用下)进行如下偶联反应，得到式I所示化合物；
The present invention also provides a preparation method of the compound shown in formula I, which comprises the following steps: in a solvent (such as a mixed solvent of N,N-dimethylformamide and water), combining the compound shown in formula II with formula III The compound shown (for example under the action of DIPEA) is subjected to the following coupling reaction to obtain the compound shown in formula I;
其中，Hal为卤素(例如Br)；其他各变量的定义如本发明任一方案所述。Wherein, Hal is a halogen (such as Br); the definitions of other variables are as described in any scheme of the present invention.
本发明还提供一种药物组合物，其包含如上所述的式I所示的化合物或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，和药学上可接受的辅料。The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I or its pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereoisomer, tautomer Isomers or solvates, and pharmaceutically acceptable excipients.
本发明还提供了一种如上所述的药物组合物在制备治疗精神疾病或神经退行性疾病的药物中的用途。The present invention also provides a use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating mental diseases or neurodegenerative diseases.
本发明还提供了一种如上所述的式I所示的化合物或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物在制备治疗精神疾病或神经退行性疾病的药物中的用途。The present invention also provides a compound represented by the above-mentioned formula I or its pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereoisomer, tautomer or solvent Use of compounds in the preparation of medicines for treating mental illnesses or neurodegenerative diseases.
在一些实施方案中，所述精神疾病或神经退行性疾病为精神分裂症、抑郁症或帕金森氏症。In some embodiments, the psychiatric or neurodegenerative disease is schizophrenia, depression, or Parkinson's disease.
术语定义Definition of Terms
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
在本发明中，术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下：结构表示环A上的氢原子被m个R1所取代，此外，当环A为双环并环 时，双环中的任一个环都可以被取代，例如，若无特别说明，结构表示环A1和/或环A2上的氢原子被m个R1所取代。In the present invention, the term "substituted" or "substituent" is a group in which a hydrogen atom is replaced by the designated group. When no substitution site is specified, substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on the ring A is replaced by m R 1 , in addition, when the ring A is bicyclic and ring When , any ring in the bicyclic ring can be substituted, for example, unless otherwise specified, The structure indicates that the hydrogen atoms on ring A1 and/or ring A2 are replaced by m R1 .
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为不存在时，表示该连接基团为单键，例如A-L-Z中L为不存在时形成的结构为A-Z。When the number of a linking group is absent, it means that the linking group is a single bond, for example, the structure formed when L is absent in A-L-Z is A-Z.
在本发明中，术语“烷基”是指饱和的直链或支链的一价烃基。C1-C6烷基是指具有1-6个碳原子的烷基，其优选为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. C 1 -C 6 alkyl refers to an alkyl group having 1-6 carbon atoms, which is preferably C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl or tert-butyl.
在本发明中，术语“卤代烷基”是指烷基中的一个或多个(例如2、3、4、5或6)氢原子被卤素所取代形成的基团，其中每个卤素独立地为F、Cl、Br或I。卤代C1-C6烷基是指被一个或多个卤素取代的C1-C6烷基，其中C1-C6烷基的定义如前所述。In the present invention, the term "haloalkyl" refers to a group formed by replacing one or more (for example, 2, 3, 4, 5 or 6) hydrogen atoms in the alkyl group with halogen, wherein each halogen is independently F, Cl, Br or I. Halogenated C 1 -C 6 alkyl refers to C 1 -C 6 alkyl substituted by one or more halogens, wherein the definition of C 1 -C 6 alkyl is as described above.
在本发明中，术语“烷氧基”是指-O-烷基，其中烷基的定义如前所述。C1-C6烷氧基是指-O-(C1-C6烷基)，其中C1-C6烷基的定义如前所述。In the present invention, the term "alkoxy" refers to -O-alkyl, wherein the definition of alkyl is as described above. C 1 -C 6 alkoxy refers to -O-(C 1 -C 6 alkyl), wherein the definition of C 1 -C 6 alkyl is as described above.
在本发明中，术语“碳环”是指由碳原子形成的饱和、部分不饱和或芳香性的单环或多环(例如并环、螺环或桥环)环状基团。在饱和的碳环中，环上的每个碳原子均是饱和的，饱和的碳环的实例包括但不限于在芳香性的碳环中，每个环均是芳香性的，芳香性的碳环的实例包括但不限于在部分不饱和的碳环中，环上至少有一个碳原子是饱和的且至少有一个碳原子是不饱和的，部分不饱和的碳环的实例包括但不限于3-8元碳环具体可以为3、4、5、6、7或8元碳环。In the present invention, the term "carbocycle" refers to a saturated, partially unsaturated or aromatic monocyclic or polycyclic (eg, asymmetric, spiro or bridged) cyclic group formed of carbon atoms. In a saturated carbocycle, each carbon atom on the ring is saturated. Examples of saturated carbocycles include, but are not limited to In an aromatic carbocycle, each ring is aromatic, examples of aromatic carbocycles include, but are not limited to In a partially unsaturated carbocycle, at least one carbon atom in the ring is saturated and at least one carbon atom is unsaturated. Examples of partially unsaturated carbocycles include, but are not limited to The 3-8 membered carbocycle can specifically be 3, 4, 5, 6, 7 or 8 membered carbocycle.
在本发明中，术语“杂环”是指由碳原子和至少一个杂原子形成的饱和、部分不饱和或芳香性的单环或多环(例如并环、螺环或桥环)环状基团，其中杂原子独立地选自N、O和S。在饱和的杂环中，环上的碳原子和杂原子均是饱和的，饱和的杂环的实例包括但不限于 在芳香性的杂环中，每个环均是芳香性的，芳香性的杂环的实例包括但不限于 在部分不饱和的杂环中，环上至少有一个原子是饱和的且至少有一个原子是不饱和的，部分不饱和的杂环的实例包括但不限于 3-8元杂环具体可以为3、4、5、6、7或8元杂环。5-7元杂环具体可以为5、6或7元杂环。In the present invention, the term "heterocycle" refers to a saturated, partially unsaturated or aromatic monocyclic or polycyclic (such as a ring, spiro or bridged ring) cyclic group formed by carbon atoms and at least one heteroatom A group wherein the heteroatoms are independently selected from N, O and S. In a saturated heterocyclic ring, both the carbon atoms and the heteroatoms on the ring are saturated, examples of saturated heterocyclic rings include but are not limited to In aromatic heterocycles, each ring is aromatic, examples of aromatic heterocycles include but are not limited to In a partially unsaturated heterocyclic ring, at least one atom of the ring is saturated and at least one atom is unsaturated. Examples of partially unsaturated heterocyclic rings include, but are not limited to Specifically, the 3-8 membered heterocycle can be 3, 4, 5, 6, 7 or 8 membered heterocycle. The 5-7 membered heterocycle may specifically be a 5, 6 or 7 membered heterocycle.
在本发明中，术语“芳环”是指芳香性的碳环，其中的每个环均是芳香性的。6-10元芳环具体可以为苯环或萘环。In the present invention, the term "aromatic ring" refers to an aromatic carbocyclic ring in which each ring is aromatic. Specifically, the 6-10 membered aromatic ring may be a benzene ring or a naphthalene ring.
在本发明中，术语“杂芳环”是指芳香性的杂环，其中的每个环均是芳香性的。杂芳环的实例包括但不限于 5-10元杂芳环具体可以为5、6、7、8、9或10元杂芳环。In the present invention, the term "heteroaromatic ring" refers to an aromatic heterocyclic ring in which each ring is aromatic. Examples of heteroaromatic rings include, but are not limited to The 5-10 membered heteroaryl ring can specifically be a 5, 6, 7, 8, 9 or 10 membered heteroaryl ring.
在本发明中，术语“双环并环”是指由两个单环构成的并环，其与其他结构的连接位点可以位于任一单环上。8-11元双环并环具体可以为8、9、10或11元双环并环。In the present invention, the term "bicyclic double ring" refers to a double ring composed of two single rings, and its connection site with other structures can be located on any single ring. The 8-11 membered bicyclo can be specifically 8, 9, 10 or 11 membered bicyclo.
在本发明中，术语“环烷基”是指单环或多环(例如并环、螺环或桥环)的一价烃基，其中的每个碳原子均是饱和的。3-8元环烷基具体可以为3、4、5、6、7或8元环烷基，包括环丙基、环丁基、 环戊基、环己基等。环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、 In the present invention, the term "cycloalkyl" refers to a monocyclic or polycyclic (eg fused, spiro or bridged) monovalent hydrocarbon group in which each carbon atom is saturated. The 3-8 membered cycloalkyl group can specifically be 3, 4, 5, 6, 7 or 8 membered cycloalkyl groups, including cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, etc. Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
本发明的化合物和它们的结构还表示包括所有异构体(包括立体异构体和互变异构体，其中立体异构体例如对映异构体、非对映异构体、几何异构体(如顺反异构体)和构象异构体)形式。它们可以根据对于氨基酸的绝对立体化学定义为(R)-/(S)-或者(D)-/(L)-或者(R,R)-/(R,S)-/(S,S)-。本发明包括所有这些可能的异构体，以及它们的外消旋的、对映体富集的和任选的纯的形式。旋光(+)和(-)，(R)-和(S)-以及(R,R)-/(R,S)-/(S,S)-或(D)-和(L)-异构体可以使用手性原料合成、手性拆分制备，或者可以使用常规技术例如但不限于使用手性柱的高效液相(HPLC)拆分。当本文所述的化合物包含烯基双键或其他几何不对称中心时，除非另有说明，所述化合物包括E和Z几何异构体两者。化学结构中，键并未指定构型，即如果化学结构中存在构型异构，键可以为或者同时包含两种构型。同样，还包括所有互变异构体形式。The compounds of the present invention and their structures also represent all isomers (including stereoisomers and tautomers, wherein stereoisomers such as enantiomers, diastereomers, geometric isomers isomers (such as cis-trans isomers) and conformational isomers) forms. They can be defined according to the absolute stereochemistry for amino acids as (R)-/(S)- or (D)-/(L)- or (R,R)-/(R,S)-/(S,S) -. The present invention includes all such possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms. Optical rotation (+) and (-), (R)- and (S)- and (R,R)-/(R,S)-/(S,S)- or (D)- and (L)-iso Constructs can be prepared using chiral starting materials synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using chiral columns. When the compounds described herein contain alkenyl double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds include both E and Z geometric isomers. chemical structure, bond configuration is not specified, i.e. if there is configurational isomerism in the chemical structure, the bond can be or both Two configurations. Likewise, all tautomeric forms are also included.
在本发明中，术语“互变异构体”指质子从分子的一个原子从原位置移动到同一分子的另一个位置上。本发明包括任何所述化合物的互变异构体。In the present invention, the term "tautomer" refers to the movement of a proton from one atom of a molecule from its original position to another position of the same molecule. The present invention includes tautomers of any of said compounds.
在本发明中，术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本发明的结构，除了用“氘”或“氚”代替氢，或者用18F-氟标记(18F同位素)代替氟，或者用11C-，13C-，或者14C-富集的碳(11C-，13C-，或者14C-碳标记；11C-，13C-，或者14C-同位素)代替碳原子的化合物处于本发明的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。在本发明中，所述的同位素衍生物例如为氘代物。In the present invention, the term "isotopically derivative" refers to a compound whose structure differs only by the presence of one or more isotopically enriched atoms. For example, having the structure of the present invention, except replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with 18 F-fluorine label ( 18 F isotope), or replacing fluorine with 11 C-, 13 C-, or 14 C-rich Compounds in which a set of carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace the carbon atoms are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. In the present invention, the isotopic derivatives are, for example, deuterated compounds.
在本发明中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。In the present invention, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing Adverse biological reaction or interaction in an adverse manner with any component contained in the composition.
在本发明中，术语“药学上可接受的盐”表示由适宜的非毒性有机酸、无机酸、有机碱或无机碱与化合物形成的盐，其保留化合物的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸，优选甲磺酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸，优选盐酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱，优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡 啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱，优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。In the present invention, the term "pharmaceutically acceptable salt" means a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with a compound, which retains the biological activity of the compound. Described organic acid can be various organic acids that can form salt conventionally in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid, and salicylic acid. The inorganic acid may be various inorganic acids conventional in the art capable of forming salts, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base can be various organic bases that are conventional in the art and can form salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines kind. The tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine One or more of pyridines. Described inorganic base can be various inorganic bases that can form salt conventionally in the art, preferably alkali metal hydride, hydroxide of alkali metal, alkoxide of alkali metal, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate One or more of , potassium bicarbonate and sodium bicarbonate. The alkali metal hydride is preferably sodium hydride and/or potassium hydride. The hydroxide of the alkali metal is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.
本发明中，术语“溶剂化物”表示化合物或其盐与适宜的溶剂形成的物质。所述的溶剂较佳地为水或有机溶剂。In the present invention, the term "solvate" means a compound or a salt thereof with a suitable solvent. The solvent is preferably water or an organic solvent.
本发明中，术语“患者”包括任何动物，优选哺乳动物，更优选人。In the present invention, the term "patient" includes any animal, preferably a mammal, more preferably a human.
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明的化合物对诸如精神分裂症、抑郁症、帕金森氏症等多种精神疾病和神经退行性疾病具有优异的药效，从而可作为治疗上述疾病的有效药物。The positive and progressive effect of the present invention is that the compound of the present invention has excellent pharmacological effects on various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease, etc., so it can be used as an effective drug for treating the above diseases .
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
以下实施例中反应过夜为12-18小时。In the following examples, the overnight reaction is 12-18 hours.
实施例1：化合物7-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-喹啉-2(1H)-酮(I-A1)的制备
Example 1: Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-quinoline- Preparation of 2(1H)-ketone (I-A1)
步骤1：LRQ-04-148的合成参照专利WO2006064355A2。1H NMR(800MHz,CDCl3)δ7.66(s,1H),7.23(t,J＝7.9Hz,1H),7.18–7.15(m,1H),6.89–6.85(m,1H),4.02(s,3H),3.75(d,J＝1.2Hz,2H).HRMS(ESI)C11H10NO2 +[M+H]+计算值：188.0706,实测值：188.0702。Step 1: Synthesis of LRQ-04-148 refers to patent WO2006064355A2. 1 H NMR (800MHz, CDCl 3 ) δ7.66(s, 1H), 7.23(t, J=7.9Hz, 1H), 7.18–7.15(m, 1H), 6.89–6.85(m, 1H), 4.02( s, 3H), 3.75 (d, J= 1.2Hz , 2H ). HRMS (ESI ) Calcd. for C11H10NO2 + [M+H] + : 188.0706, found: 188.0702.
步骤2：LRQ-04-149的合成参照专利WO2006064355A2。1H NMR(800MHz,CDCl3)δ7.64(s,1H),7.25–7.20(m,1H),7.17(t,J＝7.8Hz,1H),6.84–6.79(m,1H),3.99(s,3H),3.30(t,J＝7.1Hz,2H),3.21–3.18(m,2H).HRMS(ESI)C11H14NO2 +[M+H]+计算值：192.1019,实测值：192.1019。Step 2: Synthesis of LRQ-04-149 refers to patent WO2006064355A2. 1 H NMR (800MHz, CDCl 3 ) δ7.64(s, 1H), 7.25–7.20(m, 1H), 7.17(t, J=7.8Hz, 1H), 6.84–6.79(m, 1H), 3.99( s,3H),3.30(t,J＝7.1Hz,2H),3.21–3.18(m,2H).HRMS(ESI)C 11 H 14 NO 2 + [M+H] + calculated value: 192.1019, measured value : 192.1019.
步骤3：将LRQ-04-149(500mg,2.62mmol)和Et3N(796mg,7.86mmol)溶于二氯甲烷(10 mL)后，加入(Boc)2O(714mg,3.27mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到白色固体LRQ-04-150，无需纯化直接投入下一步反应。HRMS(ESI)C16H22NO4 +[M+H]+计算值：292.1543，实测值：292.1549。Step 3: LRQ-04-149 (500 mg, 2.62 mmol) and Et 3 N (796 mg, 7.86 mmol) were dissolved in dichloromethane (10 mL), (Boc) 2 O (714mg, 3.27mmol) was added and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain LRQ-04-150 as a white solid. Purified directly into the next reaction. HRMS (ESI) calcd for C16H22NO4 + [M+H] + : 292.1543 , found : 292.1549.
步骤4：将LRQ-04-150和多聚甲醛(157mg,5.24mmol)溶于甲苯(10mL)后，加入对甲苯磺酸(25mg,0.13mmol)，回流反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到白色固体LRQ-04-151，无需纯化直接投入下一步反应。HRMS(ESI)C17H22NO4 +[M+H]+计算值：304.1543，实测值：304.1545。Step 4: After LRQ-04-150 and paraformaldehyde (157mg, 5.24mmol) were dissolved in toluene (10mL), p-toluenesulfonic acid (25mg, 0.13mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain LRQ-04-151 as a white solid. Purified directly into the next reaction. HRMS (ESI) calcd for C17H22NO4 + [M+H] + : 304.1543 , found : 304.1545.
步骤5：将LRQ-04-151溶于4M氯化氢的二氧六环溶液中(8mL)后，室温下反应过夜。反应完毕后将溶剂减压蒸除，剩余物溶于乙醚(8mL)中，室温下搅拌15分钟后抽滤，滤渣用乙醚淋洗，减压下干燥得到白色固体LRQ-04-153(202mg，三步反应收率38％)。1H NMR(800MHz,MeOH-d4)δ7.22(t,J＝7.9Hz,1H),7.16–7.11(m,1H),6.97–6.93(m,1H),4.45(s,2H),3.97(s,3H),3.61(t,J＝6.0Hz,2H),3.07–3.01(m,2H).13C NMR(201MHz,MeOH-d4)δ146.92,145.61,145.53,129.59,125.35,112.87,112.35,108.77,56.60,43.13,41.95,19.03.HRMS(ESI)C12H14NO2 +[M+H]+计算值：204.1019,实测值：204.1016。Step 5: LRQ-04-151 was dissolved in 4M hydrogen chloride in dioxane solution (8 mL), and reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then filtered with suction, the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-04-153 (202 mg, Three-step reaction yield 38%). 1 H NMR (800MHz, MeOH-d 4 )δ7.22(t, J=7.9Hz, 1H), 7.16–7.11(m, 1H), 6.97–6.93(m, 1H), 4.45(s, 2H), 3.97(s,3H),3.61(t,J=6.0Hz,2H),3.07–3.01(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ146.92,145.61,145.53,129.59,125.35,112.87 , 112.35, 108.77, 56.60, 43.13, 41.95, 19.03. HRMS (ESI) Calculated for C 12 H 14 NO 2 + [M+H] + : 204.1019, Found: 204.1016.
步骤6：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(119mg，收率58％)。1H NMR(800MHz,MeOH-d4)δ7.79–7.71(m,1H),7.45(d,J＝8.6Hz,1H),7.14–7.07(m,1H),7.01(d,J＝7.5Hz,1H),6.85–6.72(m,3H),6.46–6.39(m,1H),4.07(t,J＝5.5Hz,2H),3.96(s,3H),3.71(s,2H),2.96–2.83(m,2H),2.78–2.66(m,4H),1.94–1.76(m,4H).13C NMR(201MHz,MeOH-d4)δ165.02,161.97,150.89,145.68,144.26,141.87,140.60,129.93,129.73,123.88,117.73,114.93,113.27,112.28,111.75,106.83,99.26,68.39,57.53,56.36,50.83,50.39,27.48,24.04,20.90.HRMS(ESI)C25H27N2O4 +[M+H]+计算值：419.1965，实测值：419.1971。HPLC:99.54％(λ＝254nm,tR＝11.18min)。Step 6: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (119 mg, yield 58%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.79–7.71(m,1H),7.45(d,J=8.6Hz,1H),7.14–7.07(m,1H),7.01(d,J=7.5 Hz,1H),6.85–6.72(m,3H),6.46–6.39(m,1H),4.07(t,J＝5.5Hz,2H),3.96(s,3H),3.71(s,2H),2.96 –2.83(m,2H),2.78–2.66(m,4H),1.94–1.76(m,4H). 13 C NMR(201MHz,MeOH-d 4 )δ165.02,161.97,150.89,145.68,144.26,141.87,140.60 ,129.93,129.73,123.88,117.73,114.93,113.27,112.28,111.75,106.83,99.26,68.39,57.53,56.36,50.83,50.39,27.48,24.04,20.90.HRMS( ESI)C 25 H 27 N 2 O 4 + [M+H] + Calculated: 419.1965, Found: 419.1971. HPLC: 99.54% (λ=254nm, tR =11.18min).
实施例2：化合物7-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(I-A2)的制备
Example 2: Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-A2)
将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47 mmol)，7-(4-溴丁氧基)-3,4-二氢喹啉-2(1H)-酮(220mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(113mg，收率55％)。1H NMR(800MHz,CDCl3)δ8.77(s,1H),7.13(t,J＝7.8Hz,1H),7.05–6.97(m,2H),6.76(d,J＝7.9Hz,1H),6.53–6.48(m,1H),6.39–6.34(m,1H),3.99(s,3H),3.95(t,J＝6.1Hz,2H),3.72(s,2H),2.90–2.83(m,4H),2.73(t,J＝5.4Hz,2H),2.71–2.66(m,2H),2.62–2.58(m,2H),1.87–1.80(m,2H),1.80–1.74(m,2H).13C NMR(201MHz,CDCl3)δ172.24,158.70,151.21,145.25,143.72,138.28,129.74,128.66,123.30,115.78,111.86,111.30,108.86,106.03,102.36,67.89,57.04,56.10,50.43,50.11,31.16,27.17,24.64,23.93,20.87.HRMS(ESI)C25H29N2O4 +[M+H]+计算值：421.2122，实测值：421.2123。HPLC:97.33％(λ＝254nm,tR＝11.25min)。After LRQ-04-153 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47 mmol), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (220mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a white solid was obtained (113 mg, yield 55%). 1 H NMR (800MHz, CDCl 3 ) δ8.77(s, 1H), 7.13(t, J=7.8Hz, 1H), 7.05–6.97(m, 2H), 6.76(d, J=7.9Hz, 1H) ,6.53–6.48(m,1H),6.39–6.34(m,1H),3.99(s,3H),3.95(t,J＝6.1Hz,2H),3.72(s,2H),2.90–2.83(m ,4H),2.73(t,J＝5.4Hz,2H),2.71–2.66(m,2H),2.62–2.58(m,2H),1.87–1.80(m,2H),1.80–1.74(m,2H ). 13 C NMR (201MHz, CDCl 3 ) δ172.24, 158.70, 151.21, 145.25, 143.72, 138.28, 129.74, 128.66, 123.30, 115.78, 111.86, 111.30, 108.86, 106.03, 10 2.36, 67.89, 57.04, 56.10, 50.43, 50.11 , 31.16, 27.17, 24.64 , 23.93, 20.87. HRMS (ESI) Calculated for C25H29N2O4 + [M+H] + : 421.2122, Found: 421.2123. HPLC: 97.33% (λ=254nm, tR =11.25min).
实施例3：化合物6-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)吲哚-2-酮(I-A3)的制备
Example 3: Compound 6-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)indole-2 - Preparation of ketone (I-A3)
步骤1：将6-羟基吲哚啉-2-酮(2.17g，14.55mmol)溶于DMF(40mL)后，依次加入K2CO3(2.1g，14.55mmol)，1,4-二溴丁烷(9.42g，43.65mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到红棕色固体LRQ-05-62(0.25g，收率6％)。1H NMR(800MHz,CDCl3)δ8.47(s,1H),7.11–7.07(m,1H),6.55–6.50(m,1H),6.47(d,J＝1.6Hz,1H),3.97(t,J＝6.0Hz,2H),3.52–3.45(m,4H),2.09–2.04(m,2H),1.96–1.90(m,2H).13C NMR(201MHz,CDCl3)δ178.61,159.29,143.59,125.28,117.21,107.92,97.74,67.30,35.78,33.52,29.57,27.98.HRMS(ESI)C12H15BrNO2 +[M+H]+计算值：284.0281，实测值：284.0289.Step 1: After dissolving 6-hydroxyindolin-2-one (2.17g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutyl Alkanes (9.42g, 43.65mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain reddish-brown solid LRQ-05-62 (0.25g, yield 6%). 1 H NMR (800MHz, CDCl 3 ) δ8.47(s, 1H), 7.11–7.07(m, 1H), 6.55–6.50(m, 1H), 6.47(d, J=1.6Hz, 1H), 3.97( t,J＝6.0Hz,2H),3.52–3.45(m,4H),2.09–2.04(m,2H),1.96–1.90(m,2H). 13 C NMR(201MHz,CDCl 3 )δ178.61,159.29, 143.59,125.28,117.21,107.92,97.74,67.30,35.78,33.52,29.57,27.98.HRMS(ESI)C 12 H 15 BrNO 2 + [M+H] + Calculated: 284.0281, Found: 284.0289.
步骤2：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，LRQ-05-62(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(46mg，收率23％)。1H NMR(800MHz,CDCl3)δ7.72(s,1H),7.14(t,J＝7.8Hz,1H),7.07(d,J＝8.2Hz,1H),7.04(d,J＝7.7Hz,1H),6.78(d,J＝7.9Hz,1H),6.54–6.50(m,1H),6.43(d,J＝2.0Hz,1H),4.03–3.95(m,5H),3.76(s,2H),3.46–3.40(m,2H),2.96–2.90(m,2H),2.80–2.70(m,4H),1.88–1.84(m,2H),1.83–1.80(m,2H).13C NMR(201MHz,CDCl3)δ175.12,159.33,148.50,145.32,143.85,143.56,129.93,125.24,123.49,117.14,111.87,111.37,107.81, 106.23,97.75,67.96,57.42,56.16,50.42,49.87,35.69,29.83,27.11,20.50.HRMS(ESI)C24H27N2O4 +[M+H]+计算值：407.1965，实测值：407.1966。HPLC:96.65％(λ＝254nm,tR＝11.28min)。Step 2: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol) and LRQ-05-62 (209mg, 0.74mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (46 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 ) δ7.72(s, 1H), 7.14(t, J=7.8Hz, 1H), 7.07(d, J=8.2Hz, 1H), 7.04(d, J=7.7Hz ,1H),6.78(d,J=7.9Hz,1H),6.54–6.50(m,1H),6.43(d,J=2.0Hz,1H),4.03–3.95(m,5H),3.76(s, 2H),3.46–3.40(m,2H),2.96–2.90(m,2H),2.80–2.70(m,4H),1.88–1.84(m,2H),1.83–1.80(m,2H). 13 C NMR (201MHz, CDCl 3 )δ175.12, 159.33, 148.50, 145.32, 143.85, 143.56, 129.93, 125.24, 123.49, 117.14, 111.87, 111.37, 107.81, 106.23,97.75,67.96,57.42,56.16,50.42,49.87,35.69,29.83,27.11,20.50.HRMS(ESI)C 24 H 27 N 2 O 4 + [M+H] + Calculated: 407.1965, Found: 407.1966 . HPLC: 96.65% (λ=254nm, tR =11.28min).
实施例4：化合物7-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-1-甲基喹啉-2(1H)-酮(I-A4)的制备
Example 4: Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-1-methyl Preparation of quinolin-2(1H)-one (I-A4)
步骤1：将7-羟基-1-甲基喹啉-2(1H)-酮(2.55g，14.55mmol)溶于DMF(40mL)后，依次加入K2CO3(2.1g，14.55mmol)，1,4-二溴丁烷(9.42g，43.65mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-05-59(2.16g，收率48％)。1H NMR(800MHz,CDCl3)δ7.59(d,J＝9.4Hz,1H),7.45(d,J＝8.5Hz,1H),6.82–6.79(m,1H),6.79–6.76(m,1H),6.55(d,J＝9.4Hz,1H),4.13–4.06(m,2H),3.68(s,3H),3.54–3.24(m,2H),2.13–2.04(m,2H),2.03–1.94(m,2H).13C NMR(201MHz,CDCl3)δ162.89,161.21,141.85,138.85,130.23,118.69,115.11,110.00,99.42,67.21,33.39,30.19,29.63,27.94.HRMS(ESI)C14H17BrNO2 +[M+H]+计算值：310.0437，实测值：310.0441.Step 1: After dissolving 7-hydroxy-1-methylquinolin-2(1H)-one (2.55g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol) successively, 1,4-Dibromobutane (9.42g, 43.65mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4) to obtain LRQ-05-59 (2.16 g, yield 48%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ7.59(d, J=9.4Hz, 1H), 7.45(d, J=8.5Hz, 1H), 6.82–6.79(m, 1H), 6.79–6.76(m, 1H), 6.55(d, J=9.4Hz, 1H), 4.13–4.06(m, 2H), 3.68(s, 3H), 3.54–3.24(m, 2H), 2.13–2.04(m, 2H), 2.03 –1.94(m,2H) .13 C NMR(201MHz,CDCl 3 )δ162.89,161.21,141.85,138.85,130.23,118.69,115.11,110.00,99.42,67.21,33.39,30.19,29.63,27.94 .HRMS(ESI)C 14 H 17 BrNO 2 + [M+H] + calcd: 310.0437, found: 310.0441.
步骤2：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，LRQ-05-59(228mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(108mg，收率51％)。1H NMR(800MHz,CDCl3)δ7.56(d,J＝9.4Hz,1H),7.42(d,J＝8.6Hz,1H),7.12(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.82–6.78(m,1H,1H),6.77–6.74(m,2H),6.52(d,J＝9.3Hz,1H),4.11(t,J＝6.2Hz,2H),3.98(s,3H),3.72(s,2H),3.65(s,3H),2.89(t,J＝5.4Hz,2H),2.76–2.68(m,4H),1.94–1.87(m,2H),1.85–1.79(m,2H).13C NMR(201MHz,CDCl3)δ162.87,161.33,151.12,145.25,143.71,141.76,138.83,130.14,129.68,123.34,118.44,114.95,111.85,111.27,110.05,106.02,99.36,68.10,56.97,56.09,50.51,50.06,29.55,27.19,23.89,20.88.HRMS(ESI)C26H29N2O4 +[M+H]+计算值：433.2122，实测值：433.2125。HPLC:97.65％(λ＝254nm,tR＝12.43min)。Step 2: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol) and LRQ-05-59 (228mg, 0.74mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (108 mg, yield 51%). 1 H NMR (800MHz, CDCl 3 ) δ7.56(d, J=9.4Hz, 1H), 7.42(d, J=8.6Hz, 1H), 7.12(t, J=7.8Hz, 1H), 7.02(d ,J=7.7Hz,1H),6.82–6.78(m,1H,1H),6.77–6.74(m,2H),6.52(d,J=9.3Hz,1H),4.11(t,J=6.2Hz, 2H), 3.98(s, 3H), 3.72(s, 2H), 3.65(s, 3H), 2.89(t, J＝5.4Hz, 2H), 2.76–2.68(m, 4H), 1.94–1.87(m ,2H),1.85–1.79(m,2H). 13 C NMR(201MHz,CDCl 3 )δ162.87,161.33,151.12,145.25,143.71,141.76,138.83,130.14,129.68,123.34,118.44,114. 95,111.85,111.27, 110.05,106.02,99.36,68.10,56.97,56.09,50.51,50.06,29.55,27.19,23.89,20.88.HRMS(ESI)C 26 H 29 N 2 O 4 + [M+H] + Calculated: 433.2122, found : 433.2125. HPLC: 97.65% (λ=254nm, tR =12.43min).
实施例5：化合物7-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-2H-苯并吡喃-2-酮(I-A5)的制备 Example 5: Compound 7-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-2H-benzene Preparation of pyran-2-one (I-A5)
步骤1：将7-羟基香豆素(2.36g，14.55mmol)溶于DMF(40mL)后，依次加入K2CO3(2.1g，14.55mmol)，1,4-二溴丁烷(9.42g，43.65mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到白色固体LRQ-05-40(2.37g，收率55％)。1H NMR(800MHz,CDCl3)δ7.63(d,J＝9.4Hz,1H),7.38–7.34(m,1H),6.84–6.81(m,1H),6.79(d,J＝2.3Hz,1H),6.24(d,J＝9.4Hz,1H),4.05(t,J＝6.1Hz,2H),3.49(t,J＝6.6Hz,2H),2.11–2.05(m,2H),2.02–1.96(m,2H).13C NMR(201MHz,CDCl3)δ162.20,161.30,156.02,143.50,128.90,113.28,112.99,112.71,101.50,67.66,33.31,29.44,27.79.HRMS(ESI)C13H14BrO3 +[M+H]+计算值：297.0121，实测值：297.0429。Step 1: After 7-hydroxycoumarin (2.36g, 14.55mmol) was dissolved in DMF (40mL), K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutane (9.42g , 43.65mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain white solid LRQ-05-40 (2.37g, yield 55%). 1 H NMR (800MHz, CDCl 3 ) δ7.63(d, J=9.4Hz, 1H), 7.38–7.34(m, 1H), 6.84–6.81(m, 1H), 6.79(d, J=2.3Hz, 1H), 6.24(d, J=9.4Hz, 1H), 4.05(t, J=6.1Hz, 2H), 3.49(t, J=6.6Hz, 2H), 2.11–2.05(m, 2H), 2.02– 1.96(m,2H) .13 C NMR(201MHz,CDCl 3 )δ162.20,161.30,156.02,143.50,128.90,113.28,112.99,112.71,101.50,67.66,33.31,29.44,27.79.HRMS(ES I) C 13 H 14 BrO 3 + [M+H] + calcd: 297.0121, found: 297.0429.
步骤2：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，LRQ-05-40(219mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(117mg，收率57％)。1H NMR(800MHz,CDCl3)δ7.60(d,J＝9.4Hz,1H),7.33(d,J＝8.6Hz,1H),7.13(t,J＝7.8Hz,1H),7.04–7.00(m,1H),6.84–6.80(m,1H),6.79(d,J＝2.1Hz,1H),6.76(d,J＝7.9Hz,1H),6.24–6.19(m,1H),4.06(t,J＝6.2Hz,2H),3.99(s,3H),3.72(s,2H),2.89(t,J＝5.3Hz,2H),2.77–2.67(m,4H),1.93–1.85(m,2H),1.84–1.73(m,2H).13C NMR(201MHz,CDCl3)δ162.36,161.37,155.99,151.13,145.28,143.75,143.53,129.73,128.83,123.34,113.07,113.05,112.56,111.88,111.33,106.06,101.45,68.36,56.95,56.13,50.51,50.12,26.98,23.87,20.89.HRMS(ESI)C25H26NO5 +[M+H]+计算值：420.1805，实测值：420.1807。HPLC:96.57％(λ＝254nm,tR＝11.40min)。Step 2: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol) and LRQ-05-40 (219mg, 0.74mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a white solid (117 mg, yield 57%). 1 H NMR (800MHz, CDCl 3 ) δ7.60(d, J=9.4Hz, 1H), 7.33(d, J=8.6Hz, 1H), 7.13(t, J=7.8Hz, 1H), 7.04–7.00 (m,1H),6.84–6.80(m,1H),6.79(d,J=2.1Hz,1H),6.76(d,J=7.9Hz,1H),6.24–6.19(m,1H),4.06( t,J=6.2Hz,2H),3.99(s,3H),3.72(s,2H),2.89(t,J=5.3Hz,2H),2.77–2.67(m,4H),1.93–1.85(m ,2H),1.84–1.73(m,2H). 13 C NMR(201MHz,CDCl 3 )δ162.36,161.37,155.99,151.13,145.28,143.75,143.53,129.73,128.83,123.34,113.07,113. 05,112.56,111.88, 111.33, 106.06, 101.45 , 68.36, 56.95, 56.13, 50.51, 50.12, 26.98, 23.87, 20.89. HRMS (ESI) Calculated for C25H26NO5 + [ M +H] + : 420.1805, found: 420.1807. HPLC: 96.57% (λ=254nm, tR =11.40min).
实施例6：化合物8-甲氧基-2-(4-(喹啉-7-基氧基)丁基)-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶(I-A6)的制备
Example 6: Compound 8-methoxy-2-(4-(quinolin-7-yloxy)butyl)-1,2,3,4-tetrahydrobenzofuran[2,3-c] Preparation of Pyridine (I-A6)
步骤1：将7-羟基喹啉(2.11g，14.55mmol)溶于DMF(40mL)后，依次加入K2CO3(2.1g， 14.55mmol)，1,4-二溴丁烷(9.42g，43.65mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-05-52(2.52g，收率62％)。1H NMR(800MHz,CDCl3)δ8.82(d,J＝2.8Hz,1H),8.07(d,J＝8.0Hz,1H),7.74–7.66(m,1H),7.40(d,J＝1.9Hz,1H),7.27–7.25(m,1H),7.23–7.16(m,1H),4.15(t,J＝6.1Hz,2H),3.50(t,J＝6.6Hz,2H),2.16–2.06(m,2H),2.06–1.98(m,2H).13C NMR(201MHz,CDCl3)δ160.04,150.57,149.90,135.92,128.96,123.68,120.15,119.11,107.95,67.23,33.47,29.65,27.88.HRMS(ESI)C13H15BrNO+[M+H]+计算值：280.0332，实测值：280.0339。Step 1: After dissolving 7-hydroxyquinoline (2.11g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutane (9.42g, 43.65mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4) to obtain yellow solid LRQ-05-52 (2.52 g, yield 62%). 1 H NMR (800MHz, CDCl 3 ) δ8.82(d, J=2.8Hz, 1H), 8.07(d, J=8.0Hz, 1H), 7.74–7.66(m, 1H), 7.40(d, J= 1.9Hz, 1H), 7.27–7.25(m, 1H), 7.23–7.16(m, 1H), 4.15(t, J＝6.1Hz, 2H), 3.50(t, J＝6.6Hz, 2H), 2.16– 2.06(m,2H),2.06–1.98(m,2H). 13 C NMR(201MHz,CDCl 3 )δ160.04,150.57,149.90,135.92,128.96,123.68,120.15,119.11,107.95,67.23,33.47, 29.65,27.88 .HRMS (ESI) calcd for C13H15BrNO + [M+H] + : 280.0332, found: 280.0339.
步骤2：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，LRQ-05-52(206mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(110mg，收率56％)。1H NMR(800MHz,CDCl3)δ8.81–8.75(m,1H),8.06–7.99(m,1H),7.66(d,J＝8.9Hz,1H),7.39(d,J＝2.2Hz,1H),7.24–7.20(m,1H),7.20–7.15(m,1H),7.11(t,J＝7.8Hz,1H),7.01(d,J＝7.6Hz,1H),6.76–6.71(m,1H),4.14(t,J＝6.3Hz,2H),3.97(s,3H),3.70(s,2H),2.85(t,J＝5.6Hz,2H),2.71(t,J＝5.5Hz,2H),2.70–2.67(m,2H),1.95–1.88(m,2H),1.85–1.78(m,2H).13C NMR(201MHz,CDCl3)δ160.11,151.31,150.45,149.88,145.20,143.67,135.79,129.74,128.83,123.53,123.21,120.14,118.93,111.83,111.26,107.84,105.96,67.88,57.07,56.05,50.41,50.15,26.98,24.03,20.90.HRMS(ESI)C25H27N2O3 +[M+H]+计算值：403.2016，实测值：403.2011。HPLC:96.75％(λ＝254nm,tR＝10.06min)。Step 2: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol) and LRQ-05-52 (206mg, 0.74mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (110 mg, yield 56%). 1 H NMR (800MHz, CDCl 3 ) δ8.81–8.75(m,1H),8.06–7.99(m,1H),7.66(d,J=8.9Hz,1H),7.39(d,J=2.2Hz, 1H),7.24–7.20(m,1H),7.20–7.15(m,1H),7.11(t,J＝7.8Hz,1H),7.01(d,J＝7.6Hz,1H),6.76–6.71(m ,1H),4.14(t,J=6.3Hz,2H),3.97(s,3H),3.70(s,2H),2.85(t,J=5.6Hz,2H),2.71(t,J=5.5Hz ,2H),2.70–2.67(m,2H),1.95–1.88(m,2H),1.85–1.78(m,2H). 13 C NMR(201MHz,CDCl 3 )δ160.11,151.31,150.45,149.88,145.20, 143.67,135.79,129.74,128.83,123.53,123.21,120.14,118.93,111.83,111.26,107.84,105.96,67.88,57.07,56.05,50.41,50.15,26.98,2 4.03, 20.90. HRMS (ESI) C 25 H 27 N 2 O 3 + [M+H] + calculated: 403.2016, found: 403.2011. HPLC: 96.75% (λ=254nm, tR =10.06min).
实施例7：化合物2-(4-(苯并[d]噻唑-5-基氧基)丁基)-8-甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶(I-A7)的制备
Example 7: Compound 2-(4-(benzo[d]thiazol-5-yloxy)butyl)-8-methoxy-1,2,3,4-tetrahydrobenzofurano[2, 3-c] Preparation of pyridine (I-A7)
步骤1：将5-羟基苯并噻唑(2.20g，14.55mmol)溶于DMF(40mL)后，依次加入K2CO3(2.1g，14.55mmol)，1,4-二溴丁烷(9.42g，43.65mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到无色油状液体LRQ-04-02(2.96g，收率72％)。1H NMR(800MHz,CDCl3)δ8.97(s,1H),7.81–7.78(m,1H),7.61–7.57(m,1H),7.10–7.06(m,1H),4.09(t,J＝6.1Hz,2H),3.50(t,J＝6.7Hz,2H),2.14–2.06(m,2H),2.03–1.97(m,2H).13C NMR(201MHz, CDCl3)δ158.37,155.11,154.72,125.74,122.19,116.52,106.55,67.44,33.52,29.64,27.98.HRMS(ESI)C11H13BrNOS+[M+H]+计算值：285.9896，实测值：285.9897.Step 1: After dissolving 5-hydroxybenzothiazole (2.20g, 14.55mmol) in DMF (40mL), add K 2 CO 3 (2.1g, 14.55mmol), 1,4-dibromobutane (9.42g , 43.65mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain colorless oily liquid LRQ-04-02 (2.96g, yield 72%). 1 H NMR (800MHz, CDCl 3 )δ8.97(s,1H),7.81–7.78(m,1H),7.61–7.57(m,1H),7.10–7.06(m,1H),4.09(t,J ＝6.1Hz, 2H), 3.50(t, J＝6.7Hz, 2H), 2.14–2.06(m, 2H), 2.03–1.97(m, 2H). 13 C NMR(201MHz, CDCl 3 )δ158.37, 155.11, 154.72, 125.74, 122.19, 116.52, 106.55, 67.44, 33.52, 29.64, 27.98. HRMS (ESI) C 11 H 13 BrNOS + [M+H] + calculated value: 285.9896, measured value: 285.9897 .
步骤2：将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，LRQ-04-02(210mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(92mg，收率46％)。1H NMR(800MHz,CDCl3)δ8.96(s,1H),7.80–7.76(m,1H),7.59(d,J＝2.3Hz,1H),7.13(t,J＝7.8Hz,1H),7.11–7.06(m,1H),7.03(d,J＝7.7Hz,1H),6.77(d,J＝7.9Hz,1H),4.10(t,J＝6.2Hz,2H),4.00(s,3H),3.78(s,2H),2.97–2.90(m,2H),2.80–2.72(m,4H),1.95–1.89(m,2H),1.89–1.82(m,2H).13C NMR(201MHz,CDCl3)δ158.48,155.04,154.74,145.31,143.83,129.67,125.61,123.38,122.14,116.57,111.88,111.35,111.30,106.56,106.16,68.12,56.92,56.15,50.40,50.03,27.12,23.91,20.68.HRMS(ESI)C23H25N2O3S+[M+H]+计算值：409.1580，实测值：409.1587。HPLC:95.00％(λ＝254nm,tR＝11.37min)。Step 2: After dissolving LRQ-04-153 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol) and LRQ-04-02 (210mg, 0.74mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (92 mg, yield 46%). 1 H NMR (800MHz, CDCl 3 ) δ8.96(s, 1H), 7.80–7.76(m, 1H), 7.59(d, J=2.3Hz, 1H), 7.13(t, J=7.8Hz, 1H) ,7.11–7.06(m,1H),7.03(d,J=7.7Hz,1H),6.77(d,J=7.9Hz,1H),4.10(t,J=6.2Hz,2H),4.00(s, 3H), 3.78(s,2H), 2.97–2.90(m,2H), 2.80–2.72(m,4H), 1.95–1.89( m ,2H), 1.89–1.82(m,2H). 201MHz, CDCl 3 )δ158.48, 155.04, 154.74, 145.31, 143.83, 129.67, 125.61, 123.38, 122.14, 116.57, 111.88, 111.35, 111.30, 106.56, 106.16, 68.1 2,56.92,56.15,50.40,50.03,27.12,23.91,20.68 .HRMS (ESI) calcd for C23H25N2O3S + [M+H] + : 409.1580 , found : 409.1587. HPLC: 95.00% (λ=254nm, tR =11.37min).
实施例8：化合物7-(3-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙氧基)喹啉-2(1H)-酮(I-A8)的制备Example 8: Compound 7-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propoxy)quinoline-2 Preparation of (1H)-ketone (I-A8)
将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)喹啉-2(1H)-酮(208mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(48mg，收率24％)。1H NMR(800MHz,CDCl3)δ11.84(s,1H),7.70(d,J＝9.4Hz,1H),7.43(d,J＝9.3Hz,1H),7.13(t,J＝7.8Hz,1H),7.04(d,J＝7.7Hz,1H),6.84–6.80(m,2H),6.77(d,J＝7.9Hz,1H),6.52(d,J＝9.4Hz,1H),4.17(t,J＝6.1Hz,2H),4.00(s,3H),3.74(s,2H),2.90(t,J＝5.5Hz,2H),2.83(t,J＝7.2Hz,2H),2.78–2.73(m,2H),2.14–2.08(m,2H).13C NMR(201MHz,CDCl3)δ164.85,161.44,145.32,143.78,140.93,140.41,139.38,129.85,129.21,123.32,118.18,114.35,112.56,111.97,111.36,106.05,99.25,66.58,56.17,54.06,50.62,50.35,27.38,21.05.HRMS(ESI)C24H25N2O4 +[M+H]+计算值：405.1809，实测值：405.1811。HPLC:97.28％(λ＝254nm,tR＝11.56min)。After LRQ-04-153 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one ( 208mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (48 mg, yield 24%). 1 H NMR (800MHz, CDCl 3 ) δ11.84(s, 1H), 7.70(d, J=9.4Hz, 1H), 7.43(d, J=9.3Hz, 1H), 7.13(t, J=7.8Hz ,1H),7.04(d,J=7.7Hz,1H),6.84–6.80(m,2H),6.77(d,J=7.9Hz,1H),6.52(d,J=9.4Hz,1H),4.17 (t,J=6.1Hz,2H),4.00(s,3H),3.74(s,2H),2.90(t,J=5.5Hz,2H),2.83(t,J=7.2Hz,2H),2.78 –2.73(m,2H),2.14–2.08(m,2H) .13C NMR(201MHz, CDCl3 )δ164.85,161.44,145.32,143.78,140.93,140.41,139.38,129.85,129.21,123.32,118.1 8,114.35, 112.56,111.97,111.36,106.05,99.25,66.58,56.17,54.06,50.62,50.35,27.38,21.05. HRMS(ESI)C 24 H 25 N 2 O 4 + [M+H] + Calculated: 405.1809, found : 405.1811. HPLC: 97.28% (λ=254nm, tR =11.56min).
实施例9：化合物7-(3-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-A9)的制备 Example 9: Compound 7-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-A9)
将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)-3,4-二氢喹啉-2(1H)-酮(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(46mg，收率23％)。1H NMR(800MHz,CDCl3)δ8.08(s,1H),7.14(t,J＝7.8Hz,1H),7.05–7.02(m,2H),6.77(d,J＝7.9Hz,1H),6.55–6.51(m,1H),6.35–6.32(m,1H),4.03(t,J＝6.2Hz,2H),4.00(s,3H),3.72(s,2H),2.91–2.86(m,5H),2.80(t,J＝7.2Hz,2H),2.73(t,J＝5.3Hz,2H),2.63–2.59(m,2H),2.11–1.98(m,2H).13C NMR(201MHz,CDCl3)δ171.83,158.73,151.45,145.31,143.76,138.23,129.83,128.80,123.33,115.95,111.94,111.34,108.81,106.03,102.38,66.36,56.15,54.08,50.59,50.31,31.23,27.46,24.73,21.04.HRMS(ESI)C24H27N2O4 +[M+H]+计算值：407.1965，实测值：407.1958。HPLC:96.06％(λ＝254nm,tR＝11.55min)。After LRQ-04-153 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)-3,4-dihydroquinoline- 2(1H)-ketone (209mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (46 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 ) δ8.08(s, 1H), 7.14(t, J=7.8Hz, 1H), 7.05–7.02(m, 2H), 6.77(d, J=7.9Hz, 1H) ,6.55–6.51(m,1H),6.35–6.32(m,1H),4.03(t,J＝6.2Hz,2H),4.00(s,3H),3.72(s,2H),2.91–2.86(m ,5H), 2.80(t, J=7.2Hz, 2H), 2.73(t, J=5.3Hz, 2H), 2.63–2.59(m,2H), 2.11–1.98(m,2H). 13 C NMR( 201MHz, CDCl 3 )δ171.83, 158.73, 151.45, 145.31, 143.76, 138.23, 129.83, 128.80, 123.33, 115.95, 111.94, 111.34, 108.81, 106.03, 102.38, 66.3 6, 56.15, 54.08, 50.59, 50.31, 31.23, 27.46, 24.73 , 21.04 . HRMS (ESI) calcd for C24H27N2O4 + [M+H] + : 407.1965 , found : 407.1958. HPLC: 96.06% (λ=254nm, tR =11.55min).
实施例10：化合物(E)-7-((4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁-2-烯-1-基)氧基)喹啉-2(1H)-酮(I-A10)的制备Example 10: Compound (E)-7-((4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butan-2 Preparation of -en-1-yl)oxy)quinolin-2(1H)-one (I-A10)
将LRQ-04-153(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，(E)-7-(4-溴代丁-2-烯-1-基)氧基)喹啉-2(1H)-酮(217mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(150mg，收率74％)。1H NMR(800MHz,CDCl3)δ12.27(s,1H),7.70(d,J＝9.4Hz,1H),7.43(d,J＝8.6Hz,1H),7.12(t,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),6.85(s,1H),6.84–6.79(m,1H),6.75(d,J＝7.9Hz,1H),6.55(d,J＝9.4Hz,1H),6.08–6.01(m,1H),5.98–5.91(m,1H),4.71–4.61(m,2H),3.99(s,3H),3.72(s,2H),3.33(d,J＝6.4Hz,2H),2.91–2.84(m,2H),2.72(t,J＝5.2Hz,2H).13C NMR(201MHz,CDCl3)δ165.02,160.92,151.36,145.30,143.76,140.86,140.45,131.59,129.82,129.20,128.14,123.29,118.29,114.45,112.89,111.88,111.33,106.05,99.44,68.51,59.02,56.15,50.17,50.02,20.95.HRMS(ESI)C25H25N2O4 +[M+H]+计算值：417.1809，实测值：417.1811。HPLC:99.16％(λ＝254nm,tR＝11.76min)。 After LRQ-04-153 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), (E)-7-(4-bromobut-2-en-1-yl )oxy)quinolin-2(1H)-one (217mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (150 mg, yield 74%). 1 H NMR (800MHz, CDCl 3 ) δ12.27(s, 1H), 7.70(d, J=9.4Hz, 1H), 7.43(d, J=8.6Hz, 1H), 7.12(t, J=7.8Hz ,1H),7.01(d,J=7.7Hz,1H),6.85(s,1H),6.84–6.79(m,1H),6.75(d,J=7.9Hz,1H),6.55(d,J= 9.4Hz,1H),6.08–6.01(m,1H),5.98–5.91(m,1H),4.71–4.61(m,2H),3.99(s,3H),3.72(s,2H),3.33(d , J＝6.4Hz, 2H), 2.91–2.84 (m, 2H), 2.72 (t, J＝5.2Hz, 2H). 13 C NMR (201MHz, CDCl 3 ) δ165.02, 160.92, 151.36, 145.30, 143.76, 140.86 ,140.45,131.59,129.82,129.20,128.14,123.29,118.29,114.45,112.89,111.88,111.33,106.05,99.44,68.51,59.02,56.15,50.17,50.02, 20.95. HRMS(ESI)C 25 H 25 N 2 O 4 + [M+H] + Calculated: 417.1809, Found: 417.1811. HPLC: 99.16% (λ=254nm, tR =11.76min).
实施例11：化合物N-(反式-4-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己基)乙酰胺(I-A11)的制备Example 11: Compound N-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl) ) cyclohexyl) acetamide (I-A11) preparation
步骤1：将NaOH(62mg,1.56mmol)溶于H2O(10mL)后，依次加入K2CO3(440mg,3.16mmol)，反式-(N-BOC-4-氨基环己基)乙酸(200mg,0.78mmol)和溴苄(540mg,3.16mmol)，回流反应3小时。反应完毕后降温至室温，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到白色固体LRQ-04-11(220mg，收率83％)。1H NMR(800MHz,CDCl3)δ7.38–7.30(m,5H),5.10(s,2H),4.37(s,1H),3.42–3.29(m,1H),2.24(d,J＝6.8Hz,2H),2.03–1.92(m,2H),1.82–1.70(m,3H),1.43(s,9H),1.16–1.00(m,4H).13C NMR(201MHz,CDCl3)δ172.79,155.33,136.15,128.68(2C),128.33,128.30(2C),79.22,66.25,49.58,41.52,34.18(2C),33.25,31.71(2C),28.56(3C).HRMS(ESI)C20H29NO4Na+[M+H]+计算值：370.1989，实测值：370.1988。Step 1: After dissolving NaOH (62mg, 1.56mmol) in H 2 O (10mL), add K 2 CO 3 (440mg, 3.16mmol), trans-(N-BOC-4-aminocyclohexyl)acetic acid ( 200mg, 0.78mmol) and benzyl bromide (540mg, 3.16mmol), reflux for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether =1:2), to obtain white solid LRQ-04-11 (220 mg, yield 83%). 1 H NMR (800MHz, CDCl 3 ) δ7.38–7.30(m,5H), 5.10(s,2H), 4.37(s,1H), 3.42–3.29(m,1H), 2.24(d,J=6.8 Hz,2H),2.03–1.92(m,2H),1.82–1.70(m,3H),1.43(s,9H),1.16–1.00(m,4H). 13 C NMR(201MHz,CDCl 3 )δ172. 79,155.33,136.15,128.68(2C),128.33,128.30(2C),79.22,66.25,49.58,41.52,34.18(2C),33.25,31.71(2C),28.56(3C).HRMS(ESI)C 20 H 29 NO 4 Na + [M+H] + calcd: 370.1989, found: 370.1988.
步骤2：将LRQ-04-11(200mg,0.63mmol)溶于THF(10mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(1.9mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(5mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到白色固体LRQ-04-12-Boc，无需纯化直接投入下一步反应。HRMS(ESI)C13H26NO3 +[M+H]+计算值：244.1907，实测值：244.1910。Step 2: Dissolve LRQ-04-11 (200mg, 0.63mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (1.9mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (5 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a white solid LRQ- 04-12-Boc, directly put into the next reaction without purification. HRMS (ESI) calcd for C13H26NO3 + [M+H] + : 244.1907 , found : 244.1910.
步骤3：将LRQ-04-12-Boc溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(500mg,1.41mmol)和三苯基膦(500mg,1.88mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体LRQ-04-152-Boc(113mg，收率59％)。1H NMR(800MHz,CDCl3)δ3.45–3.39(m,2H),3.39–3.33(m,1H),2.04–1.95(m,2H),1.81–1.72(m,4H),1.50–1.37(m,10H),1.14–1.06(m,2H),1.06–0.97(m,2H).13C NMR(201MHz,CDCl3)δ155.37,79.22,49.88,39.68,35.38,33.33(2C),31.87,31.30(2C),28.58(3C).HRMS(ESI)C13H25BrNO2 +[M+H]+计算值：306.1063，实测值：306.1066。 Step 3: Dissolve LRQ-04-12-Boc in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (500mg, 1.41mmol) and triphenylphosphine (500mg, 1.88mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1) to obtain white solid LRQ-04-152-Boc (113 mg, yield 59%). 1 H NMR (800MHz, CDCl 3 ) δ3.45–3.39(m,2H),3.39–3.33(m,1H),2.04–1.95(m,2H),1.81–1.72(m,4H),1.50–1.37 (m,10H),1.14–1.06(m,2H),1.06–0.97(m,2H). 13 C NMR(201MHz,CDCl 3 )δ155.37,79.22,49.88,39.68,35.38,33.33(2C), 31.87, 31.30 (2C), 28.58 (3C). HRMS (ESI) Calcd. for C13H25BrNO2+ [ M + H] + : 306.1063, found: 306.1066.
步骤4：将LRQ-04-152-Boc(113mg,0.38mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂得到无色油状液体LRQ-04-12-NH2，无需纯化直接投入下一步反应。HRMS(ESI)C8H17BrN+[M+H]+计算值：206.0539，实测值：206.0541。Step 4: Dissolve LRQ-04-152-Boc (113mg, 0.38mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid LRQ-04-12-NH2, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C8H17BrN + [M+H] + : 206.0539, found : 206.0541.
步骤5：将LRQ-04-12-NH2溶于DCM(10mL)后，依次加入三乙胺(115mg,1.14mmol)和乙酰氯(33mg,0.42mmol)，室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体LRQ-05-70(43mg，收率46％)。1H NMR(800MHz,CDCl3)δ5.48–5.27(m,1H),3.74–3.64(m,1H),3.42(t,J＝7.0Hz,2H),2.01–1.96(m,2H),1.94(s,3H),1.80–1.73(m,4H),1.48–1.41(m,1H),1.14–1.08(m,2H),1.08–1.01(m,2H).13C NMR(201MHz,CDCl3)δ169.34,48.63,39.59,35.29,32.97(2C),31.86,31.17(2C),23.70.HRMS(ESI)C10H19BrNO+[M+H]+计算值：248.0645，实测值：248.0638。Step 5: After LRQ-04-12-NH2 was dissolved in DCM (10 mL), triethylamine (115 mg, 1.14 mmol) and acetyl chloride (33 mg, 0.42 mmol) were added successively, and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:1) to obtain LRQ-05-70 (43 mg, yield 46%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ5.48–5.27(m,1H),3.74–3.64(m,1H),3.42(t,J＝7.0Hz,2H),2.01–1.96(m,2H), 1.94(s,3H), 1.80–1.73(m,4H), 1.48–1.41(m,1H), 1.14–1.08(m,2H), 1.08–1.01(m,2H). 13 C NMR (201MHz, CDCl 3 ) δ169.34, 48.63, 39.59, 35.29, 32.97(2C), 31.86, 31.17(2C), 23.70. HRMS (ESI) C 10 H 19 BrNO + [M+H] + calculated value: 248.0645, measured value: 248.0638.
步骤6：将LRQ-04-153(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-05-70(42mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(20mg，收率44％)。1H NMR(800MHz,CDCl3)δ7.12(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.79–6.71(m,1H),5.37(d,J＝8.0Hz,1H),3.98(s,3H),3.74–3.62(m,3H),2.83(t,J＝5.5Hz,2H),2.71(t,J＝5.4Hz,2H),2.65–2.58(m,2H),2.01–1.94(m,2H),1.93(s,3H),1.81–1.74(m,2H),1.53–1.46(m,2H),1.31–1.26(m,1H),1.11–1.04(m,4H).13C NMR(201MHz,CDCl3)δ169.35,151.31,145.26,143.72,129.78,123.29,111.86,111.30,106.02,56.12,55.31,50.46,50.23,48.73,35.26,34.36,33.15(2C),31.95(2C),23.67,20.89.HRMS(ESI)C22H31N2O3 +[M+H]+计算值：371.2329，实测值：371.2333。HPLC:96.63％(λ＝254nm,tR＝10.56min)。Step 6: After dissolving LRQ-04-153 (24mg, 0.12mmol) in DMF (8mL), add DIPEA (45mg, 0.35mmol) and LRQ-05-70 (42mg, 0.17mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (20 mg, yield 44%). 1 H NMR (800MHz, CDCl 3 ) δ7.12(t, J=7.8Hz, 1H), 7.02(d, J=7.7Hz, 1H), 6.79–6.71(m, 1H), 5.37(d, J= 8.0Hz, 1H), 3.98(s, 3H), 3.74–3.62(m, 3H), 2.83(t, J＝5.5Hz, 2H), 2.71(t, J＝5.4Hz, 2H), 2.65–2.58( m,2H),2.01–1.94(m,2H),1.93(s,3H),1.81–1.74(m,2H),1.53–1.46(m,2H),1.31–1.26(m,1H),1.11– 1.04(m,4H) .13C NMR(201MHz,CDCl 3 )δ169.35,151.31,145.26,143.72,129.78,123.29,111.86,111.30,106.02,56.12,55.31,50.46,50.23,48.7 3,35.26,34.36,33.15( 2C), 31.95 (2C) , 23.67 , 20.89 . HRMS (ESI) Calcd. for C22H31N2O3 + [M+H] + : 371.2329, found: 371.2333. HPLC: 96.63% (λ=254nm, tR =10.56min).
实施例12：化合物3-(反式-4-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-A12)的制备Example 12: Compound 3-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A12)
步骤1：将LRQ-04-12-NH2溶于DCM(10mL)后，依次加入三乙胺(115mg,1.14mmol)和二甲氨基甲酰氯(45mg,0.42mmol)，室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体LRQ-04-152(42mg，收率40％)。1H NMR(800MHz,CDCl3)δ4.14(s,1H),3.61–3.53(m,1H),3.43(t,J＝7.0Hz,2H),2.87(s,6H),2.06–1.97(m,2H),1.80–1.71(m,4H),1.48–1.39(m,1H),1.14–0.99(m,4H).13C NMR(201MHz,CDCl3)δ157.92, 49.84,39.67,36.27(2C),35.46,33.88(2C),32.01,31.39(2C).HRMS(ESI)C11H22BrN2O+[M+H]+计算值：277.0910，实测值：277.0911。Step 1: Dissolve LRQ-04-12-NH2 in DCM (10mL), add triethylamine (115mg, 1.14mmol) and dimethylcarbamoyl chloride (45mg, 0.42mmol) successively, and react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:1) to obtain LRQ-04-152 (42 mg, yield 40%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ 4.14(s, 1H), 3.61–3.53(m, 1H), 3.43(t, J=7.0Hz, 2H), 2.87(s, 6H), 2.06–1.97( m,2H),1.80–1.71(m,4H),1.48–1.39(m,1H),1.14–0.99(m,4H). 13 C NMR(201MHz,CDCl 3 )δ157.92, 49.84,39.67,36.27(2C),35.46,33.88(2C),32.01,31.39(2C).HRMS(ESI)C 11 H 22 BrN 2 O + [M+H] + Calculated: 277.0910, Found: 277.0911 .
步骤2：将LRQ-04-153(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(17mg，收率35％)。1H NMR(800MHz,CDCl3)δ7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.77–6.73(m,1H),4.13(d,J＝7.5Hz,1H),3.98(s,3H),3.67(s,2H),3.60–3.52(m,1H),2.86(s,6H),2.84(t,J＝5.5Hz,2H),2.74–2.67(m,2H),2.66–2.58(m,2H),2.02–1.98(m,2H),1.80–1.76(m,2H),1.54–1.46(m,2H),1.30–1.25(m,1H),1.11–1.04(m,4H).13C NMR(201MHz,CDCl3)δ157.94,151.31,145.26,143.73,129.79,123.27,111.86,111.30,106.01,56.12,55.41,50.45,50.24,49.93,36.24(2C),35.45,34.39,34.07(2C),32.17(2C),20.89.HRMS(ESI)C23H34N3O3 +[M+H]+计算值：400.2595，实测值：400.2608。HPLC:98.43％(λ＝254nm,tR＝10.65min)。Step 2: After dissolving LRQ-04-153 (24mg, 0.12mmol) in DMF (8mL), add DIPEA (45mg, 0.35mmol) and LRQ-04-152 (47mg, 0.17mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a yellow solid (17 mg, yield 35%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.11(t, J=7.8Hz, 1H), 7.02(d, J=7.7Hz, 1H), 6.77–6.73(m, 1H), 4.13(d, J= 7.5Hz, 1H), 3.98(s, 3H), 3.67(s, 2H), 3.60–3.52(m, 1H), 2.86(s, 6H), 2.84(t, J＝5.5Hz, 2H), 2.74– 2.67(m,2H),2.66–2.58(m,2H),2.02–1.98(m,2H),1.80–1.76(m,2H),1.54–1.46(m,2H),1.30–1.25(m,1H ),1.11–1.04(m,4H). 13 C NMR(201MHz,CDCl 3 )δ157.94,151.31,145.26,143.73,129.79,123.27,111.86,111.30,106.01,56.12,55.41,50.45,50. 24,49.93,36.24( 2C), 35.45, 34.39 , 34.07(2C), 32.17(2C), 20.89. HRMS (ESI) Calculated for C23H34N3O3 + [ M +H] + : 400.2595, found: 400.2608. HPLC: 98.43% (λ=254nm, tR =10.65min).
实施例13：化合物N-(反式-4-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己基)甲磺酰胺(I-A13)的制备Example 13: Compound N-(trans-4-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) methanesulfonamide (I-A13) preparation
步骤1：将LRQ-04-12-NH2溶于DCM(10mL)后，依次加入三乙胺(115mg,1.14mmol)和甲基磺酰氯(48mg,0.42mmol)，室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体LRQ-05-71(53mg，收率49％)。1H NMR(800MHz,CDCl3)δ4.33–4.22(m,1H),3.42(t,J＝7.0Hz,2H),3.30–3.20(m,1H),2.97(s,3H),2.11–2.01(m,2H),1.85–1.79(m,2H),1.78–1.71(m,2H),1.52–1.40(m,1H),1.34–1.19(m,2H),1.11–0.96(m,2H).13C NMR(201MHz,CDCl3)δ53.26,42.37,39.42,34.97,34.25(2C),31.60,31.20(2C).HRMS(ESI)C9H19BrNO2S+[M+H]+计算值：284.0314，实测值：284.0317。Step 1: After LRQ-04-12-NH2 was dissolved in DCM (10 mL), triethylamine (115 mg, 1.14 mmol) and methanesulfonyl chloride (48 mg, 0.42 mmol) were added successively, and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:1) to obtain LRQ-05-71 (53 mg, yield 49%) as a white solid. 1 H NMR (800MHz, CDCl 3 ) δ4.33–4.22(m,1H),3.42(t,J=7.0Hz,2H),3.30–3.20(m,1H),2.97(s,3H),2.11– 2.01(m,2H),1.85–1.79(m,2H),1.78–1.71(m,2H),1.52–1.40(m,1H),1.34–1.19(m,2H),1.11–0.96(m,2H ) .13 C NMR(201MHz,CDCl 3 )δ53.26,42.37,39.42,34.97,34.25(2C),31.60,31.20(2C).HRMS(ESI)C 9 H 19 BrNO 2 S + [M+H] + Calculated value: 284.0314, measured value: 284.0317.
步骤2：将LRQ-04-153(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-05-71(48mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(19mg，收率38％)。1H NMR(800MHz,CDCl3)δ7.15(t,J＝7.8Hz,1H),7.05–7.02(m,1H),6.80–6.76(m,1H),4.36–4.26(m,1H),4.00(s,3H),3.82(s,2H),3.29–3.18(m,1H),3.03–2.93(m,5H),2.83–2.77(m,2H),2.76–2.70(m,2H),2.09–2.02(m,2H),1.85–1.77(m,2H),1.59–1.51(m,2H),1.31–1.28(m,1H),1.25–1.20(m,2H),1.12–1.02(m,2H).13C  NMR(201MHz,CDCl3)δ151.31,145.34,143.91,129.40,123.57,111.83,111.38,106.37,56.17,54.75,53.28,50.29,49.70,42.26,34.82,34.35(2C),33.53,31.91(2C),20.20.HRMS(ESI)C21H31N2O4S+[M+H]+计算值：407.1999，实测值：407.1996。HPLC:99.02％(λ＝254nm,tR＝10.85min)。Step 2: After dissolving LRQ-04-153 (24mg, 0.12mmol) in DMF (8mL), add DIPEA (45mg, 0.35mmol) and LRQ-05-71 (48mg, 0.17mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (19 mg, yield 38%). 1 H NMR (800MHz, CDCl 3 ) δ7.15(t, J=7.8Hz, 1H), 7.05–7.02(m, 1H), 6.80–6.76(m, 1H), 4.36–4.26(m, 1H), 4.00(s,3H),3.82(s,2H),3.29–3.18(m,1H),3.03–2.93(m,5H),2.83–2.77(m,2H),2.76–2.70(m,2H), 2.09–2.02(m,2H),1.85–1.77(m,2H),1.59–1.51(m,2H),1.31–1.28(m,1H),1.25–1.20(m,2H),1.12–1.02(m ,2H). 13 C NMR (201MHz, CDCl 3 )δ151.31, 145.34, 143.91, 129.40, 123.57, 111.83, 111.38, 106.37, 56.17, 54.75, 53.28, 50.29, 49.70, 42.26, 34.82, 34.35 (2C) ,33.53,31.91(2C),20.20 .HRMS (ESI) calcd for C21H31N2O4S + [M+H] + : 407.1999, found : 407.1996 . HPLC: 99.02% (λ=254nm, tR =10.85min).
实施例14：化合物N-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)四氢-2H-吡喃-4-甲酰胺(I-A14)的制备Example 14: Compound N-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)tetrahydro-2H- Preparation of pyran-4-carboxamide (I-A14)
步骤1：将LRQ-04-153(340mg,1.67mmol)和DIPEA(1.3g,10.02mmol)溶于DMF(10mL)后，加入N-Boc-2-溴乙基胺(561mg,2.51mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体LRQ-05-116(200mg，收率35％)。1H NMR(800MHz,CDCl3)δ7.14(t,J＝7.8Hz,1H),7.04(d,J＝7.7Hz,1H),6.77(d,J＝7.9Hz,1H),4.00(s,3H),3.70(s,2H),3.37–3.27(m,2H),2.90–2.84(m,2H),2.78–2.69(m,4H),1.44(s,9H).HRMS(ESI)C19H27N2O4 +[M+H]+计算值：347.1965，实测值：347.1963。Step 1: After dissolving LRQ-04-153 (340mg, 1.67mmol) and DIPEA (1.3g, 10.02mmol) in DMF (10mL), add N-Boc-2-bromoethylamine (561mg, 2.51mmol), React overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1) to obtain LRQ-05-116 (200 mg, yield 35%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ7.14(t, J=7.8Hz, 1H), 7.04(d, J=7.7Hz, 1H), 6.77(d, J=7.9Hz, 1H), 4.00(s ,3H),3.70(s,2H),3.37–3.27(m,2H),2.90–2.84(m,2H),2.78–2.69(m,4H),1.44(s,9H).HRMS(ESI)C 19 H 27 N 2 O 4 + [M+H] + Calc.: 347.1965, Found: 347.1963.
步骤2：将LRQ-05-116(70mg,0.20mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(155mg,1.20mmol)和四氢-2H-吡喃-4-羰基氯(44mg,0.30mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体(48mg，收率77％)。1H NMR(800MHz,CDCl3)δ7.15(t,J＝7.8Hz,1H),7.06–7.02(m,1H),6.81–6.74(m,1H),6.18–6.09(m,1H),4.07–3.92(m,5H),3.70(s,2H),3.48–3.42(m,2H),3.42–3.34(m,2H),2.87(t,J＝5.6Hz,2H),2.76(t,J＝5.9Hz,2H),2.73(t,J＝5.3Hz,2H),2.36–2.29(m,1H),1.83–1.76(m,2H),1.75–1.70(m,2H).13C NMR(201MHz,CDCl3)δ174.47,150.99,145.36,143.75,129.65,123.49,111.97,111.31,106.19,67.41(2C),56.17,55.46,50.15,50.04,42.30,36.44,29.43(2C),20.97.HRMS(ESI)C20H27N2O4 +[M+H]+计算值：359.1965，实测值：359.1962。HPLC:98.69％(λ＝254nm,tR＝11.69min)。Step 2: Dissolve LRQ-05-116 (70mg, 0.20mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a white solid (48 mg, yield 77%). 1 H NMR (800MHz, CDCl 3 ) δ7.15(t, J=7.8Hz, 1H), 7.06–7.02(m, 1H), 6.81–6.74(m, 1H), 6.18–6.09(m, 1H), 4.07–3.92(m,5H),3.70(s,2H),3.48–3.42(m,2H),3.42–3.34(m,2H),2.87(t,J＝5.6Hz,2H),2.76(t, 13 C NMR (201MHz, CDCl 3 )δ174.47,150.99,145.36,143.75,129.65,123.49,111.97,111.31,106.19,67.41(2C),56.17,55.46,50.15,50.04,42.30,36.44, 29.43(2C), 20.97.HRMS( ESI) calcd for C20H27N2O4 + [M+H] + : 359.1965 , found: 359.1962 . HPLC: 98.69% (λ=254nm, tR =11.69min).
实施例15：化合物4,4-二氟-N-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己烷-1-甲酰胺(I-A15)的制备Example 15: Compound 4,4-difluoro-N-(2-(8-methoxy-3,4-dihydrobenzofur[2,3-c]pyridin-2(1H)-yl)ethyl Base) the preparation of cyclohexane-1-carboxamide (I-A15)
将LRQ-05-116(70mg,0.20mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(155mg,1.20mmol)和4,4-二氟环己烷甲酰氯(68mg,0.30mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体(43mg，收率63％)。1H NMR(800MHz,CDCl3)δ7.15(t,J＝7.8Hz,1H),7.06–7.01(m,1H),6.79(d,J＝7.9Hz,1H),6.17–6.07(m,1H),4.00(s,3H),3.70(s,2H),3.47–3.39(m,2H),2.87(t,J＝5.6Hz,2H),2.76(t,J＝5.9Hz,2H),2.73(t,J＝5.5Hz,2H),2.21–2.11(m,3H),1.94–1.87(m,2H),1.86–1.79(m,2H),1.76–1.65(m,2H).13C NMR(201MHz,CDCl3)δ174.23,150.98,145.37,143.76,129.64,123.51,122.79(t,J＝449.2Hz),111.97,111.32,106.20,56.17,55.44,50.14,50.06,42.88,36.47,32.98(t,J＝25.2Hz)(2C),26.07,26.02,20.97.HRMS(ESI)C21H27F2N2O3 +[M+H]+计算值：393.1984，实测值：393.1979。HPLC:99.04％(λ＝254nm,tR＝11.88min)。LRQ-05-116 (70mg, 0.20mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a white solid (43 mg, yield 63%). 1 H NMR (800MHz, CDCl 3 ) δ7.15(t, J=7.8Hz, 1H), 7.06–7.01(m, 1H), 6.79(d, J=7.9Hz, 1H), 6.17–6.07(m, 1H), 4.00(s, 3H), 3.70(s, 2H), 3.47–3.39(m, 2H), 2.87(t, J=5.6Hz, 2H), 2.76(t, J=5.9Hz, 2H), 13 C NMR (201MHz, CDCl 3 ) δ174.23, 150.98, 145.37, 143.76, 129.64, 123.51, 122.79 (t, J=449.2Hz), 111.97, 111.32, 106.20, 56.17, 55.44, 50.14, 50.06, 4 2.88, 36.47, 32.98(t , J = 25.2 Hz) (2C), 26.07 , 26.02 , 20.97. HRMS ( ESI) Calcd. for C21H27F2N2O3 + [M+H] + : 393.1984, found: 393.1979. HPLC: 99.04% (λ=254nm, tR =11.88min).
实施例16：化合物7-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)喹啉-2(1H)-酮(I-A16)的制备
Example 16: Compound 7-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)quinoline-2 Preparation of (1H)-ketone (I-A16)
步骤1：将2-(7-羟基苯并呋喃-3-基)乙酸甲酯(2.0g,9.70mmol)和K2CO3(1.3g,9.70mmol)溶于DMF(10mL)后，加入碘乙烷(4.54g,29.10mmol)，室温搅拌反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到无色油状液体LRQ-05-125(2.2g，收率97％)。1H NMR(800MHz,CDCl3)δ7.63(s,1H),7.19–7.10(m,2H),6.83–6.79(m,1H),4.25(q,J＝7.0Hz,2H),3.72(s,3H),3.70(s,2H),1.51(t,J＝7.0Hz,3H).HRMS(ESI)C13H15O4 +[M+H]+计算值：235.0965，实测值：235.0964。 Step 1: After dissolving methyl 2-(7-hydroxybenzofuran-3-yl)acetate (2.0 g, 9.70 mmol) and K 2 CO 3 (1.3 g, 9.70 mmol) in DMF (10 mL), add iodine Ethane (4.54g, 29.10mmol), stirred at room temperature overnight. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:10) to obtain colorless oily liquid LRQ-05-125 (2.2 g, yield 97%). 1 H NMR (800MHz, CDCl 3 ) δ7.63(s, 1H), 7.19–7.10(m, 2H), 6.83–6.79(m, 1H), 4.25(q, J=7.0Hz, 2H), 3.72( s,3H),3.70(s,2H),1.51(t,J＝7.0Hz,3H).HRMS(ESI)C 13 H 15 O 4 + [M+H] + calculated value: 235.0965, measured value: 235.0964 .
步骤2：将LRQ-05-125(2.2g,9.40mmol)溶于THF(10mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(28.2mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(80mL)，随后室温搅拌1小时，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到淡黄色油状液体LRQ-05-127(1.5g，收率77％)。1H NMR(800MHz,CDCl3)δ7.51(s,1H),7.17–7.12(m,2H),6.83–6.79(m,1H),4.25(q,J＝7.0Hz,2H),3.95–3.88(m,2H),2.96–2.88(m,2H),1.51(t,J＝7.0Hz,3H).HRMS(ESI)C12H15O3 +[M+H]+计算值：207.1016,实测值：207.1013。Step 2: Dissolve LRQ-05-125 (2.2g, 9.40mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (28.2mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (80mL), then stir at room temperature for 1 hour, extract with ethyl acetate (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and wash the residue with silica gel Separation and purification by column chromatography (ethyl acetate/petroleum ether=1:4) gave light yellow oily liquid LRQ-05-127 (1.5 g, yield 77%). 1 H NMR (800MHz, CDCl 3 )δ7.51(s,1H),7.17–7.12(m,2H),6.83–6.79(m,1H),4.25(q,J＝7.0Hz,2H),3.95– 3.88(m,2H),2.96–2.88(m,2H),1.51(t,J＝7.0Hz,3H).HRMS(ESI)C 12 H 15 O 3 + [M+H] + calculated value: 207.1016, Found value: 207.1013.
步骤3：将LRQ-05-127(1.5g,7.28mmol)，三苯基膦(2.86g,10.92mmol)和邻苯二甲酰亚胺(1.61g,10.92mmol)溶于四氢呋喃(50mL)后，降温至0℃，加入DEAD(1.90g,10.92mmol)。然后将反应液升温至室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-05-129，无需纯化直接投入下一步反应。HRMS(ESI)C20H18NO4 +[M+H]+计算值：336.1230，实测值：336.1224。Step 3: After dissolving LRQ-05-127 (1.5g, 7.28mmol), triphenylphosphine (2.86g, 10.92mmol) and phthalimide (1.61g, 10.92mmol) in tetrahydrofuran (50mL) , cooled to 0° C., and added DEAD (1.90 g, 10.92 mmol). Then the reaction solution was warmed to room temperature and reacted overnight. After the reaction was completed, add water (10mL) to dilute, extract with ethyl acetate (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05-129, which can be directly used without purification Next reaction. HRMS (ESI) calcd for C20H18NO4 + [M+H] + : 336.1230 , found : 336.1224.
步骤4：将LRQ-05-129溶于甲醇(80mL)和二氯甲烷(20mL)的混合溶液后，加入水合肼(911mg,18.2mmol)，回流反应过夜。反应完毕后，减压蒸除溶剂得到淡黄色油状液体LRQ-05-131，无需纯化直接投入下一步反应。HRMS(ESI)C12H16NO2 +[M+H]+计算值：206.1176，实测值：206.1182。Step 4: After LRQ-05-129 was dissolved in a mixed solution of methanol (80 mL) and dichloromethane (20 mL), hydrazine hydrate (911 mg, 18.2 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain LRQ-05-131, a light yellow oily liquid, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C12H16NO2 + [M+H] + : 206.1176, found : 206.1182 .
步骤5：将LRQ-05-131和Et3N(2.21g,21.84mmol)溶于二氯甲烷(10mL)后，加入(Boc)2O(1.99g,9.10mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到淡黄色油状液体LRQ-05-133，无需纯化直接投入下一步反应。HRMS(ESI)C17H24NO4 +[M+H]+计算值：306.1700,实测值：306.1703。Step 5: After dissolving LRQ-05-131 and Et 3 N (2.21 g, 21.84 mmol) in dichloromethane (10 mL), add (Boc) 2 O (1.99 g, 9.10 mmol) and react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05- 133, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C17H24NO4 + [M+H] + : 306.1700 , found : 306.1703.
步骤6：将LRQ-05-133和多聚甲醛(437mg,14.56mmol)溶于甲苯(20mL)后，加入对甲苯磺酸(88mg,0.51mmol)，回流反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到淡黄色油状液体LRQ-05-135(750mg，四步反应收率33％)。1H NMR(800MHz,CDCl3)δ7.13(t,J＝7.8Hz,1H),7.03(d,J＝6.9Hz,1H),6.80–6.76(m,1H),4.62(s,2H),4.30–4.20(m,2H),3.81–3.66(m,2H),2.78–2.65(m,2H),1.49(s,9H),1.28(t,J＝6.0Hz,3H).HRMS(ESI)C18H24NO4 +[M+H]+计算值：318.1700,实测值：318.1701。Step 6: After LRQ-05-133 and paraformaldehyde (437mg, 14.56mmol) were dissolved in toluene (20mL), p-toluenesulfonic acid (88mg, 0.51mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:10) to obtain LRQ-05-135 (750mg, four-step reaction yield 33%) as light yellow oily liquid. 1 H NMR (800MHz, CDCl 3 ) δ7.13(t, J=7.8Hz, 1H), 7.03(d, J=6.9Hz, 1H), 6.80–6.76(m, 1H), 4.62(s, 2H) ,4.30–4.20(m,2H),3.81–3.66(m,2H),2.78–2.65(m,2H),1.49(s,9H),1.28(t,J＝6.0Hz,3H).HRMS(ESI )C 18 H 24 NO 4 + [M+H] + calcd: 318.1700, found: 318.1701.
步骤7：将LRQ-05-135(750mg,2.36mmol)溶于4M氯化氢的二氧六环溶液中(10mL)后，室温下反应过夜。反应完毕后将溶剂减压蒸除，剩余物溶于乙醚(8mL)中，室温下搅拌15分钟后抽滤，滤渣用乙醚淋洗，减压下干燥得到白色固体LRQ-05-137(436mg，收率85％)。1H NMR(800MHz,CDCl3)δ7.12(t,J＝7.8Hz,1H),7.03(d,J＝7.7Hz,1H),6.77(d,J＝7.9Hz,1H),4.26(q,J＝7.0Hz,2H),4.04(s,2H),3.17(t,J＝5.5Hz,2H),2.78–2.65(m,2H),1.51(t,J＝7.0Hz,3H).HRMS(ESI)C13H16NO2 +[M+H]+计算值：218.1176,实测值：218.1182。Step 7: LRQ-05-135 (750 mg, 2.36 mmol) was dissolved in 4M hydrogen chloride in dioxane (10 mL), and reacted overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then filtered with suction, the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-05-137 (436 mg, Yield 85%). 1 H NMR (800MHz, CDCl 3 ) δ7.12(t, J=7.8Hz, 1H), 7.03(d, J=7.7Hz, 1H), 6.77(d, J=7.9Hz, 1H), 4.26(q ,J=7.0Hz,2H),4.04(s,2H),3.17(t,J=5.5Hz,2H),2.78–2.65(m,2H),1.51(t,J=7.0Hz,3H).HRMS (ESI) Calcd. for C13H16NO2 + [M+H] + : 218.1176, found: 218.1182 .
步骤8：将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg， 1.38mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(103mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到橙黄色固体(47mg，收率47％)。1H NMR(800MHz,CDCl3)δ7.74–7.68(m,1H),7.46–7.40(m,1H),7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.83–6.78(m,2H),6.76(d,J＝7.9Hz,1H),6.53(d,J＝9.4Hz,1H),4.25(q,J＝7.0Hz,2H),4.11(t,J＝6.2Hz,2H),3.74(s,2H),2.94–2.86(m,2H),2.79–2.67(m,4H),1.93–1.88(m,2H),1.86–1.79(m,2H),1.51(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.86,161.49,150.69,145.73,144.59,140.92,140.44,131.36,129.19,123.29,118.13,114.29,112.69,111.89,111.20,107.21,99.08,68.19,64.56,50.52,50.27,49.71,32.94,29.84,27.15,15.09.HRMS(ESI)C26H29N2O4 +[M+H]+计算值：433.2122，实测值：433.2124。HPLC:97.89％(λ＝254nm,tR＝12.44min)。Step 8: After dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol), 7-(4-bromobutoxy)quinolin-2(1H)-one (103mg, 0.35mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), an orange-yellow solid (47 mg, yield 47%) was obtained. 1 H NMR (800MHz, CDCl 3 )δ7.74–7.68(m,1H),7.46–7.40(m,1H),7.11(t,J=7.8Hz,1H),7.02(d,J=7.7Hz, 1H), 6.83–6.78(m, 2H), 6.76(d, J=7.9Hz, 1H), 6.53(d, J=9.4Hz, 1H), 4.25(q, J=7.0Hz, 2H), 4.11( t,J＝6.2Hz,2H),3.74(s,2H),2.94–2.86(m,2H),2.79–2.67(m,4H),1.93–1.88(m,2H),1.86–1.79(m, 2H), 1.51(t, J=7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ164.86, 161.49, 150.69, 145.73, 144.59, 140.92, 140.44, 131.36, 129.19, 123.29, 118.13, 114 .29,112.69, 111.89, 111.20, 107.21, 99.08, 68.19, 64.56, 50.52, 50.27, 49.71, 32.94, 29.84, 27.15, 15.09. HRMS (ESI) Calculated for C 26 H 29 N 2 O 4 + [M+H] + : 433.2122, Found value: 433.2124. HPLC: 97.89% (λ=254nm, tR =12.44min).
实施例17：化合物3-(反式-4-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-A17)的制备
Example 17: Compound 3-(trans-4-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A17)
将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-04-152(94mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体I(11mg，收率12％)。1H NMR(800MHz,CDCl3)δ7.10(t,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),6.77–6.73(m,1H),4.24(q,J＝7.0Hz,2H),3.69(s,2H),3.61–3.53(m,1H),2.87(s,6H),2.86–2.82(m,2H),2.75–2.70(m,2H),2.65–2.61(m,2H),2.02–2.00(m,2H),1.81–1.76(m,2H),1.53–1.48(m,5H),1.31–1.28(m,1H),1.10–1.05(m,4H).HRMS(ESI)C24H36N3O3 +[M+H]+计算值：414.2751，实测值：414.2748。HPLC:97.97％(λ＝254nm,tR＝12.47min)。After LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), DIPEA (178 mg, 1.38 mmol) and LRQ-04-152 (94 mg, 0.35 mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain yellow solid I (11 mg, yield 12%). 1 H NMR (800MHz, CDCl 3 ) δ7.10(t, J=7.8Hz, 1H), 7.01(d, J=7.7Hz, 1H), 6.77–6.73(m, 1H), 4.24(q, J= 7.0Hz,2H),3.69(s,2H),3.61–3.53(m,1H),2.87(s,6H),2.86–2.82(m,2H),2.75–2.70(m,2H),2.65–2.61 (m,2H),2.02–2.00(m,2H),1.81–1.76(m,2H),1.53–1.48(m,5H),1.31–1.28(m,1H),1.10–1.05(m,4H) .HRMS ( ESI ) calcd for C24H36N3O3 + [M+H] + : 414.2751 , found : 414.2748. HPLC: 97.97% (λ=254nm, tR =12.47min).
实施例18：化合物7-(4-(8-异丙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)喹啉-2(1H)-酮(I-A18)的制备
Example 18: Compound 7-(4-(8-isopropoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)quinoline- Preparation of 2(1H)-ketone (I-A18)
步骤1：将2-(7-羟基苯并呋喃-3-基)乙酸甲酯(2.0g,9.70mmol)和K2CO3(1.3g,9.70mmol)溶于DMF(10mL)后，加入2-溴丙烷(3.58g,29.10mmol)，室温搅拌反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到无色油状液体LRQ-05-126(2.3g，收率98％)。1H NMR(800MHz,CDCl3)δ7.62(s,1H),7.17–7.11(m,2H),6.85–6.81(m,1H),4.83–4.74(m,1H),3.73(s,3H),3.69(s,2H),1.42(d,J＝6.1Hz,6H).HRMS(ESI)C14H17O4 +[M+H]+计算值：249.1121，实测值：249.1115。Step 1: After dissolving methyl 2-(7-hydroxybenzofuran-3-yl)acetate (2.0 g, 9.70 mmol) and K 2 CO 3 (1.3 g, 9.70 mmol) in DMF (10 mL), add 2 -Bromopropane (3.58g, 29.10mmol), stirred at room temperature overnight. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:10) to obtain colorless oily liquid LRQ-05-126 (2.3 g, yield 98%). 1 H NMR (800MHz, CDCl 3 )δ7.62(s,1H),7.17–7.11(m,2H),6.85–6.81(m,1H),4.83–4.74(m,1H),3.73(s,3H ), 3.69 (s, 2H), 1.42 (d, J = 6.1 Hz, 6H). HRMS (ESI) Calcd for C 14 H 17 O 4 + [M+H] + : 249.1121, Found: 249.1115.
步骤2：将LRQ-05-126(2.3g,9.50mmol)溶于THF(10mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(28.5mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(80mL)，随后室温搅拌1小时，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到白色固体LRQ-05-128(1.6g，收率77％)。1H NMR(800MHz,CDCl3)δ7.51(s,1H),7.14(d,J＝4.4Hz,2H),6.85–6.81(m,1H),4.83–4.75(m,1H),3.94–3.89(m,2H),2.96–2.90(m,2H),1.43(d,J＝6.1Hz,6H).HRMS(ESI)C13H17O3 +[M+H]+计算值：221.1172，实测值：221.1171。Step 2: Dissolve LRQ-05-126 (2.3g, 9.50mmol) in THF (10mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (28.5mL, 1.0M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (80mL), then stir at room temperature for 1 hour, extract with ethyl acetate (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and wash the residue with silica gel Separation and purification by column chromatography (ethyl acetate/petroleum ether=1:4) gave white solid LRQ-05-128 (1.6 g, yield 77%). 1 H NMR (800MHz, CDCl 3 )δ7.51(s,1H),7.14(d,J=4.4Hz,2H),6.85–6.81(m,1H),4.83–4.75(m,1H),3.94– 3.89(m,2H),2.96–2.90(m,2H),1.43(d,J＝6.1Hz,6H).HRMS(ESI) Calcd for C 13 H 17 O 3 + [M+H] + : 221.1172, Measured value: 221.1171.
步骤3：将LRQ-05-128(1.6g,7.32mmol)，三苯基膦(2.88g,10.97mmol)和邻苯二甲酰亚胺(1.61g,10.97mmol)溶于四氢呋喃(50mL)后，降温至0℃，加入DEAD(1.91g,10.97mmol)。然后将反应液升温至室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到白色固体LRQ-05-130，无需纯化直接投入下一步反应。HRMS(ESI)C21H20NO4 +[M+H]+计算值：350.1387，实测值：350.1388。Step 3: After dissolving LRQ-05-128 (1.6g, 7.32mmol), triphenylphosphine (2.88g, 10.97mmol) and phthalimide (1.61g, 10.97mmol) in tetrahydrofuran (50mL) , cooled to 0° C., and added DEAD (1.91 g, 10.97 mmol). Then the reaction solution was warmed to room temperature and reacted overnight. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a white solid LRQ-05-130, which was directly put into the next step without purification reaction. HRMS (ESI) calcd for C21H20NO4 + [M+H] + : 350.1387 , found: 350.1388 .
步骤4：将LRQ-05-130溶于甲醇(80mL)和二氯甲烷(20mL)的混合溶液后，加入水合肼(916mg,18.3mmol)，回流反应过夜。反应完毕后，减压蒸除溶剂得到橙黄色固体LRQ-05-132，无需纯化直接投入下一步反应。HRMS(ESI)C13H18NO2 +[M+H]+计算值：220.1332，实测值：220.1336。Step 4: After LRQ-05-130 was dissolved in a mixed solution of methanol (80 mL) and dichloromethane (20 mL), hydrazine hydrate (916 mg, 18.3 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain an orange-yellow solid LRQ-05-132, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C13H18NO2 + [M+H] + : 220.1332 , found : 220.1336.
步骤5：将LRQ-05-132和Et3N(2.22g,21.96mmol)溶于二氯甲烷(10mL)后，加入(Boc)2O (2.00g,9.15mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到淡黄色油状液体LRQ-05-134，无需纯化直接投入下一步反应。HRMS(ESI)C18H26NO4 +[M+H]+计算值：320.1856,实测值：320.1858。Step 5: After dissolving LRQ-05-132 and Et 3 N (2.22 g, 21.96 mmol) in dichloromethane (10 mL), add (Boc) 2 O (2.00g, 9.15mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05- 134, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C18H26NO4 + [M+H] + : 320.1856 , found : 320.1858.
步骤6：将LRQ-05-134和多聚甲醛(440mg,14.64mmol)溶于甲苯(20mL)后，加入对甲苯磺酸(88mg,0.51mmol)，回流反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到淡黄色油状液体LRQ-05-136(890mg，四步反应收率37％)。1H NMR(800MHz,CDCl3)δ7.12(t,J＝7.8Hz,1H),7.02(d,J＝7.4Hz,1H),6.82–6.79(m,1H),4.83–4.75(m,1H),4.62(s,2H),3.80–3.66(m,2H),2.77–2.62(m,2H),1.49(s,10H),1.43(d,J＝6.1Hz,6H).HRMS(ESI)C19H26NO4 +[M+H]+计算值：332.1856,实测值：332.1849。Step 6: After dissolving LRQ-05-134 and paraformaldehyde (440 mg, 14.64 mmol) in toluene (20 mL), p-toluenesulfonic acid (88 mg, 0.51 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:10) to obtain LRQ-05-136 (890mg, four-step reaction yield 37%) in light yellow oily liquid. 1 H NMR (800MHz, CDCl 3 ) δ7.12(t, J=7.8Hz, 1H), 7.02(d, J=7.4Hz, 1H), 6.82–6.79(m, 1H), 4.83–4.75(m, 1H),4.62(s,2H),3.80–3.66(m,2H),2.77–2.62(m,2H),1.49(s,10H),1.43(d,J＝6.1Hz,6H).HRMS(ESI )C 19 H 26 NO 4 + [M+H] + calcd: 332.1856, found: 332.1849.
步骤7：将LRQ-05-136(890mg,2.69mmol)溶于4M氯化氢的二氧六环溶液中(10mL)后，室温下反应过夜。反应完毕后将溶剂减压蒸除，剩余物溶于乙醚(8mL)中，室温下搅拌15分钟后抽滤，滤渣用乙醚淋洗，减压下干燥得到白色固体LRQ-05-138(577mg，收率83％)。1H NMR(800MHz,CDCl3)δ7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.6Hz,1H),6.80(d,J＝7.9Hz,1H),4.80–4.75(m,1H),4.07(s,2H),3.25–3.17(m,2H),2.78–2.69(m,2H),1.42(d,J＝6.1Hz,6H).HRMS(ESI)C14H18NO2 +[M+H]+计算值：232.1332,实测值：232.1334。Step 7: LRQ-05-136 (890 mg, 2.69 mmol) was dissolved in 4M hydrogen chloride in dioxane (10 mL), and reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, then suction filtered, and the filter residue was rinsed with diethyl ether, and dried under reduced pressure to obtain a white solid LRQ-05-138 (577 mg, Yield 83%). 1 H NMR (800MHz, CDCl 3 ) δ7.11(t, J=7.8Hz, 1H), 7.02(d, J=7.6Hz, 1H), 6.80(d, J=7.9Hz, 1H), 4.80–4.75 (m,1H),4.07(s,2H),3.25–3.17(m,2H),2.78–2.69(m,2H),1.42(d,J＝6.1Hz,6H).HRMS(ESI)C 14 H 18 NO 2 + [M+H] + Calculated value: 232.1332, measured value: 232.1334.
步骤8：将LRQ-05-138(50mg，0.22mmol)溶于DMF(8mL)后，依次加入DIPEA(171mg，1.32mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(97mg，0.33mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到橙黄色固体(42mg，收率44％)。1H NMR(800MHz,CDCl3)δ7.71(d,J＝9.4Hz,1H),7.43(d,J＝9.0Hz,1H),7.10(t,J＝7.8Hz,1H),7.01(d,J＝7.6Hz,1H),6.82–6.75(m,3H),6.53(d,J＝9.4Hz,1H),4.82–4.73(m,1H),4.15–4.05(m,2H),3.75(s,2H),2.96–2.85(m,2H),2.78–2.67(m,4H),1.93–1.86(m,2H),1.86–1.78(m,2H),1.42(d,J＝6.1Hz,6H).13C NMR(201MHz,CDCl3)δ164.88,161.48,146.94,144.82,143.48,140.93,140.45,129.39,129.19,123.27,118.13,114.30,112.69,111.86,111.26,109.57,99.09,71.50,68.19,57.00,50.53,50.27,29.85,27.13,23.99,22.37(2C).HRMS(ESI)C27H31N2O4 +[M+H]+计算值：447.2278，实测值：447.2273。HPLC:97.68％(λ＝254nm,tR＝12.45min)。Step 8: After dissolving LRQ-05-138 (50mg, 0.22mmol) in DMF (8mL), add DIPEA (171mg, 1.32mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (97mg, 0.33mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), an orange-yellow solid (42 mg, yield 44%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.71(d, J=9.4Hz, 1H), 7.43(d, J=9.0Hz, 1H), 7.10(t, J=7.8Hz, 1H), 7.01(d ,J=7.6Hz,1H),6.82–6.75(m,3H),6.53(d,J=9.4Hz,1H),4.82–4.73(m,1H),4.15–4.05(m,2H),3.75( s,2H),2.96–2.85(m,2H),2.78–2.67(m,4H),1.93–1.86(m,2H),1.86–1.78(m,2H),1.42(d,J＝6.1Hz, 6H). 13 C NMR (201MHz, CDCl 3 ) δ164.88, 161.48, 146.94, 144.82, 143.48, 140.93, 140.45, 129.39, 129.19, 123.27, 118.13, 114.30, 112.69, 111.86, 111.26, 109.57, 99.09, 71.50, 68.19, 57.00, 50.53, 50.27, 29.85, 27.13, 23.99 , 22.37 (2C). HRMS (ESI) Calculated for C27H31N2O4 + [M+H] + : 447.2278 , Found: 447.2273. HPLC: 97.68% (λ=254nm, tR =12.45min).
实施例19：化合物3-(反式-4-(2-(8-异丙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-A19)的制备
Example 19: Compound 3-(trans-4-(2-(8-isopropoxy-3,4-dihydrobenzofur[2,3-c]pyridin-2(1H)-yl)B base) cyclohexyl) -1, the preparation of 1-dimethylurea (I-A19)
将LRQ-05-138(50mg，0.22mmol)溶于DMF(8mL)后，依次加入DIPEA(171mg，1.32mmol)，LRQ-04-152(89mg，0.33mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(22mg，收率24％)。1H NMR(800MHz,CDCl3)δ7.09(t,J＝7.8Hz,1H),7.01–6.98(m,1H),6.79–6.74(m,1H),4.83–4.72(m,1H),3.68(s,2H),3.62–3.51(m,1H),2.86(s,6H),2.85–2.81(m,2H),2.74–2.68(m,2H),2.66–2.58(m,2H),2.02–1.99(m,2H),1.81–1.76(m,2H),1.53–1.47(m,2H),1.40(d,J＝6.1Hz,6H),1.28(s,1H),1.09–1.05(m,4H).HRMS(ESI)C25H38N3O3 +[M+H]+计算值：428.2908，实测值：428.2901。HPLC:97.43％(λ＝254nm,tR＝12.47min)。After LRQ-05-138 (50 mg, 0.22 mmol) was dissolved in DMF (8 mL), DIPEA (171 mg, 1.32 mmol) and LRQ-04-152 (89 mg, 0.33 mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (22 mg, yield 24%). 1 H NMR (800MHz, CDCl 3 ) δ7.09(t, J=7.8Hz, 1H), 7.01–6.98(m, 1H), 6.79–6.74(m, 1H), 4.83–4.72(m, 1H), 3.68(s,2H),3.62–3.51(m,1H),2.86(s,6H),2.85–2.81(m,2H),2.74–2.68(m,2H),2.66–2.58(m,2H), 2.02–1.99(m,2H),1.81–1.76(m,2H),1.53–1.47(m,2H),1.40(d,J＝6.1Hz,6H),1.28(s,1H),1.09–1.05( m,4H). HRMS ( ESI ) calcd for C25H38N3O3 + [M+H] + : 428.2908 , found: 428.2901. HPLC: 97.43% (λ=254nm, tR =12.47min).
实施例20：化合物7-(2-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)喹啉-2(1H)-酮(I-A20)(IHCH-5219)的制备
Example 20: Compound 7-(2-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)quinoline-2( Preparation of 1H)-ketone (I-A20) (IHCH-5219)
步骤1，将3-氨基苯丁酸甲酯(1.00g，5.17mmol)溶于二氯甲烷(10mL)，降温至0℃后，依次加入吡啶(818mg，10.34mmol)和肉桂酰氯(1.29g，7.76mmol)，升温至室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到橙黄色油状液体LRQ-06-95，无需纯化直接投入下一步反应。HRMS(ESI)C20H22NO3 +[M+H]+计算值：324.1594，实测值：324.1597。Step 1, dissolve methyl 3-aminobenzenebutyrate (1.00g, 5.17mmol) in dichloromethane (10mL), cool down to 0°C, add pyridine (818mg, 10.34mmol) and cinnamoyl chloride (1.29g, 7.76 mmol), warmed up to room temperature and reacted overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10mL), extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain an orange-yellow oily liquid LRQ-06- 95, directly put into the next reaction without purification. HRMS (ESI) calcd for C20H22NO3 + [M+H]+: 324.1594, found : 324.1597 .
步骤2，将LRQ-06-95溶于氯苯(20mL)，氮气置换三次后加入三氯化铝(3.45g,25.85mmol)，升温至95℃反应3小时。反应完毕后将反应液降温至0℃，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯 /石油醚＝1:1)，得到淡黄色固体LRQ-06-96(780mg，两步反应收率61％)。1H NMR(800MHz,CDCl3)δ7.81(d,J＝9.3Hz,1H),7.50(d,J＝8.0Hz,1H),7.22(s,1H),7.10–7.07(m,1H),6.69(d,J＝9.4Hz,1H),3.68(s,3H),2.79–2.73(m,2H),2.36(t,J＝7.4Hz,2H),2.03–1.99(m,2H).HRMS(ESI)C14H16NO3 +[M+H]+计算值：246.1125，实测值：246.1119。Step 2: Dissolve LRQ-06-95 in chlorobenzene (20 mL), replace with nitrogen three times, then add aluminum trichloride (3.45 g, 25.85 mmol), heat up to 95°C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0°C, diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure. Analysis, separation and purification (ethyl acetate /petroleum ether=1:1) to obtain LRQ-06-96 (780 mg, two-step reaction yield 61%) as a light yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ7.81(d, J=9.3Hz, 1H), 7.50(d, J=8.0Hz, 1H), 7.22(s, 1H), 7.10–7.07(m, 1H) ,6.69(d,J=9.4Hz,1H),3.68(s,3H),2.79–2.73(m,2H),2.36(t,J=7.4Hz,2H),2.03–1.99(m,2H). HRMS (ESI) calcd for C14H16NO3 + [M+H]+: 246.1125 , found : 246.1119.
步骤3，将LRQ-06-96(780mg，3.18mmol)溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(10mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后，加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到黄色油状液体LRQ-06-97，无需纯化直接投入下一步反应。HRMS(ESI)C13H16NO2 +[M+H]+计算值：218.1176，实测值：218.1178。Step 3, LRQ-06-96 (780mg, 3.18mmol) was dissolved in THF (20mL), the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (10mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction is complete, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain a yellow oily liquid LRQ-06-97, directly put into the next reaction without purification. HRMS (ESI) calcd for C13H16NO2 + [M+H]+: 218.1176, found : 218.1178 .
步骤4，将LRQ-06-97溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.58g,4.77mmol)和三苯基膦(1.67g,6.36mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到淡黄色固体LRQ-06-98(45mg，两步反应收率5％)。1H NMR(600MHz,MeOH-d4)δ7.89(d,J＝9.4Hz,1H),7.58(d,J＝8.1Hz,1H),7.26(s,1H),7.13(d,J＝7.9Hz,1H),6.64(d,J＝9.4Hz,1H),3.49(t,J＝6.7Hz,2H),2.89(t,J＝7.9Hz,2H),1.97–1.92(m,2H),1.83–1.77(m,2H).HRMS(ESI)C13H15BrNO+[M+H]+计算值：280.0332，实测值：280.0328。Step 4: Dissolve LRQ-06-97 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.58g, 4.77mmol) and triphenylphosphine (1.67g, 6.36mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:2), to obtain LRQ-06-98 (45 mg, two-step reaction yield 5%) as a light yellow solid. 1 H NMR (600MHz, MeOH-d 4 ) δ7.89(d, J=9.4Hz, 1H), 7.58(d, J=8.1Hz, 1H), 7.26(s, 1H), 7.13(d, J= 7.9Hz, 1H), 6.64(d, J=9.4Hz, 1H), 3.49(t, J=6.7Hz, 2H), 2.89(t, J=7.9Hz, 2H), 1.97–1.92(m, 2H) , 1.83 - 1.77 (m,2H) . HRMS (ESI) Calcd. for C13H15BrNO + [M+H]+: 280.0332, found: 280.0328.
步骤5，将LRQ-04-153(21mg，0.10mmol)溶于DMF(8mL)后，依次加入DIPEA(84mg，0.65mmol)，LRQ-06-98(45mg，0.16mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(13mg，收率32％)。1H NMR(800MHz,CDCl3)δ12.16(s,1H),7.76(d,J＝9.4Hz,1H),7.51–7.41(m,1H),7.22(s,1H),7.12(t,J＝7.8Hz,1H),7.06(d,J＝7.9Hz,1H),7.02(d,J＝7.7Hz,1H),6.80–6.72(m,1H),6.70–6.58(m,1H),3.99(s,3H),3.68(s,2H),2.88–2.80(m,2H),2.79–2.70(m,4H),2.67–2.59(m,2H),1.78–1.69(m,2H),1.68–1.58(m,2H)13C NMR(201MHz,CDCl3)δ164.78,151.38,146.11,145.27,143.74,141.00,138.78,129.81,127.82,123.69,123.28,120.44,118.29,115.57,111.89,111.33,105.97,57.38,56.12,50.58,50.24,36.03,29.22,27.10,20.97.HRMS(ESI)C25H27N2O3 +[M+H]+计算值：403.2016，实测值：403.2011。HPLC:98.65％(λ＝254nm,tR＝11.68min)。Step 5, after dissolving LRQ-04-153 (21mg, 0.10mmol) in DMF (8mL), add DIPEA (84mg, 0.65mmol) and LRQ-06-98 (45mg, 0.16mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (13 mg, yield 32%). 1 H NMR (800MHz, CDCl 3 ) δ12.16(s, 1H), 7.76(d, J=9.4Hz, 1H), 7.51–7.41(m, 1H), 7.22(s, 1H), 7.12(t, J＝7.8Hz, 1H), 7.06(d, J＝7.9Hz, 1H), 7.02(d, J＝7.7Hz, 1H), 6.80–6.72(m, 1H), 6.70–6.58(m, 1H), 3.99(s,3H),3.68(s,2H),2.88–2.80(m,2H),2.79–2.70(m,4H),2.67–2.59(m,2H),1.78–1.69(m,2H), 1.68–1.58(m,2H) 13 C NMR(201MHz, CDCl 3 )δ164.78,151.38,146.11,145.27,143.74,141.00,138.78,129.81,127.82,123.69,123.28,120.44,118 .29, 115.57, 111.89, 111.33, 105.97 , 57.38, 56.12, 50.58, 50.24, 36.03, 29.22, 27.10, 20.97. HRMS (ESI) Calculated for C 25 H 27 N 2 O 3 + [M+H]+: 403.2016, Found: 403.2011. HPLC: 98.65% (λ=254nm, tR =11.68min).
实施例21：化合物1-((8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)环己烷-1-醇(I-A21)(IHCH-5228)的制备
Example 21: Compound 1-((8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)methyl)cyclohexane-1-ol Preparation of (I-A21)(IHCH-5228)
将LRQ-04-153(50mg,0.25mmol)溶于无水乙醇(10mL)，加入亚甲基环己烷氧化物(138mg,1.25mmol)后，升温至60℃反应过夜。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(32mg，收率42％)。1H NMR(800MHz,CDCl3)δ7.14(t,J＝7.8Hz,1H),7.07–7.02(m,1H),6.77(d,J＝7.9Hz,1H),4.00(s,3H),3.87(s,2H),3.07–2.95(m,2H),2.78–2.68(m,2H),2.57(s,2H),1.69–1.62(m,2H),1.61–1.53(m,3H),1.50–1.42(m,2H),1.39–1.32(m,2H),1.30–1.23(m,1H).13C NMR(201MHz,CDCl3)δ151.46,145.34,143.65,129.73,123.40,112.07,111.31,106.09,70.73,66.18,56.15,52.80,52.74,36.61(2C),26.00,22.25(2C),21.96.HRMS(ESI)C19H26NO3 +[M+H]+计算值：316.1907，实测值：316.1908。HPLC:97.68％(λ＝254nm,tR＝11.41min)。LRQ-04-153 (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), methylenecyclohexane oxide (138 mg, 1.25 mmol) was added, and the temperature was raised to 60° C. to react overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain a white solid (32 mg, yield 42%). 1 H NMR (800MHz, CDCl 3 ) δ7.14(t, J=7.8Hz, 1H), 7.07–7.02(m, 1H), 6.77(d, J=7.9Hz, 1H), 4.00(s, 3H) ,3.87(s,2H),3.07–2.95(m,2H),2.78–2.68(m,2H),2.57(s,2H),1.69–1.62(m,2H),1.61–1.53(m,3H) ,1.50–1.42(m,2H),1.39–1.32(m,2H),1.30–1.23(m,1H). 13 C NMR(201MHz,CDCl 3 )δ151.46,145.34,143.65,129.73,123.40,112.07,111.31 ,106.09,70.73,66.18,56.15,52.80,52.74,36.61(2C),26.00,22.25(2C),21.96.HRMS(ESI)C 19 H 26 NO 3 + [M+H] + calculated value: 316.1907, measured Value: 316.1908. HPLC: 97.68% (λ=254nm, tR =11.41min).
实施例22：化合物2-(4-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(I-A22)(IHCH-5201)的制备
Example 22: Compound 2-(4-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A22)(IHCH-5201)
步骤1，将4-甲基-2H-[1,2,4]三嗪-3,5-二酮(2.25g，17.70mmol)溶于DMF(20mL)后，依次加入NaH(0.85g，21.24mmol)，1,4-二溴丁烷(11.46g，53.10mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到淡黄色油状液体LRQ-06-15(2.19g，收率47％)。1H NMR(800MHz,CDCl3)δ7.39(s,1H),4.01(t,J＝6.7Hz,2H),3.43(t,J＝6.3Hz,2H),3.33(s,3H),1.96–1.84(m,4H).HRMS(ESI)C8H13BrN3O2 +[M+H]+计算值：262.0186，实测值：262.0188。Step 1, after dissolving 4-methyl-2H-[1,2,4]triazine-3,5-dione (2.25g, 17.70mmol) in DMF (20mL), add NaH (0.85g, 21.24 mmol), 1,4-dibromobutane (11.46g, 53.10mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain light yellow oily liquid LRQ-06-15 (2.19g, yield 47%). 1 H NMR (800MHz, CDCl 3 ) δ7.39(s, 1H), 4.01(t, J=6.7Hz, 2H), 3.43(t, J=6.3Hz, 2H), 3.33(s, 3H), 1.96 -1.84 (m,4H ) . HRMS (ESI) calcd for C8H13BrN3O2 + [M+H]+: 262.0186, found : 262.0188.
步骤2，将LRQ-04-153(50mg，0.25mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg，1.48mmol)，LRQ-06-15(97mg，0.37mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(31mg，收率33％)。1H NMR(800MHz,CDCl3)δ7.39(s,1H),7.13(t,J＝7.8Hz,1H),7.03(d,J＝7.7Hz,1H),6.78–6.74(m,1H),4.06–4.01(m,2H),3.99(s,3H),3.69(s,2H),3.33(s,3H),2.89–2.81(m,2H),2.77–2.70(m,2H),2.69–2.62(m,2H),1.88–1.80(m,2H),1.69–1.62(m,2H).13C NMR(201MHz,CDCl3)δ156.32,151.16,148.96,145.29,143.75,133.90,129.75,123.33,111.89,111.32,106.03,56.84,56.14,51.74,50.49,50.19,27.10,26.18,24.36,20.93. HRMS(ESI)C20H25N4O4 +[M+H]+计算值：385.1870，实测值：385.1865。HPLC:98.02％(λ＝254nm,tR＝10.85min)。Step 2, after LRQ-04-153 (50mg, 0.25mmol) was dissolved in DMF (8mL), DIPEA (191mg, 1.48mmol) and LRQ-06-15 (97mg, 0.37mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a light yellow solid (31 mg, yield 33%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.39(s, 1H), 7.13(t, J=7.8Hz, 1H), 7.03(d, J=7.7Hz, 1H), 6.78–6.74(m, 1H) ,4.06–4.01(m,2H),3.99(s,3H),3.69(s,2H),3.33(s,3H),2.89–2.81(m,2H),2.77–2.70(m,2H),2.69 –2.62(m,2H),1.88–1.80(m,2H),1.69–1.62(m,2H). 13 C NMR(201MHz,CDCl 3 )δ156.32,151.16,148.96,145.29,143.75,133.90,129.75,123.33 ,111.89,111.32,106.03,56.84,56.14,51.74,50.49,50.19,27.10,26.18,24.36,20.93. HRMS ( ESI ) calcd for C20H25N4O4 + [M+H]+: 385.1870 , found : 385.1865. HPLC: 98.02% (λ=254nm, tR =10.85min).
实施例23：化合物2-(3-(8-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(I-A23)(IHCH-5202)的制备
Example 23: Compound 2-(3-(8-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A23)(IHCH-5202)
步骤1，将4-甲基-2H-[1,2,4]三嗪-3,5-二酮(2.25g，17.70mmol)溶于DMF(20mL)后，依次加入NaH(0.85g，21.24mmol)，1,3-二溴丙烷(11.25g，53.10mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到无色油状液体LRQ-06-28(1.78g，收率41％)。1H NMR(800MHz,CDCl3)δ7.41(s,1H),4.04(t,J＝6.6Hz,2H),3.43(t,J＝6.2Hz,2H),3.20(s,3H),1.91–1.82(m,2H).HRMS(ESI)C7H11BrN3O2 +[M+H]+计算值：248.0029，实测值：248.0031。Step 1, after dissolving 4-methyl-2H-[1,2,4]triazine-3,5-dione (2.25g, 17.70mmol) in DMF (20mL), add NaH (0.85g, 21.24 mmol), 1,3-dibromopropane (11.25g, 53.10mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain colorless oily liquid LRQ-06-28 (1.78g, yield 41%). 1 H NMR (800MHz, CDCl 3 ) δ7.41(s, 1H), 4.04(t, J=6.6Hz, 2H), 3.43(t, J=6.2Hz, 2H), 3.20(s, 3H), 1.91 -1.82 (m,2H ) . HRMS (ESI) Calcd . for C7H11BrN3O2 + [M+H]+: 248.0029, found : 248.0031.
步骤2，将LRQ-04-153(50mg，0.25mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg，1.48mmol)，LRQ-06-28(91mg，0.37mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(35mg，收率38％)。1H NMR(800MHz,CDCl3)δ7.37(s,1H),7.12(t,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),6.75(d,J＝7.9Hz,1H),4.13–4.06(m,2H),3.99(s,3H),3.66(s,2H),3.26(s,3H),2.86–2.77(m,2H),2.71–2.66(m,4H),2.07–1.99(m,2H).13C NMR(201MHz,CDCl3)δ156.31,151.20,149.02,145.25,143.68,133.79,129.69,123.33,111.80,111.30,106.01,56.11,54.38,50.48,50.24,50.18,26.98,25.87,20.97.HRMS(ESI)C19H23N4O4 +[M+H]+计算值：371.1714，实测值：371.1712。HPLC:96.59％(λ＝254nm,tR＝10.54min)。Step 2, after dissolving LRQ-04-153 (50mg, 0.25mmol) in DMF (8mL), add DIPEA (191mg, 1.48mmol) and LRQ-06-28 (91mg, 0.37mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a yellow solid (35 mg, yield 38%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.37(s, 1H), 7.12(t, J=7.8Hz, 1H), 7.01(d, J=7.7Hz, 1H), 6.75(d, J=7.9Hz ,1H),4.13–4.06(m,2H),3.99(s,3H),3.66(s,2H),3.26(s,3H),2.86–2.77(m,2H),2.71–2.66(m,4H ),2.07–1.99(m,2H). 13 C NMR(201MHz,CDCl 3 )δ156.31,151.20,149.02,145.25,143.68,133.79,129.69,123.33,111.80,111.30,106.01,56.11,5 4.38, 50.48, 50.24, 50.18, 26.98, 25.87 , 20.97 . HRMS (ESI) Calcd. for C19H23N4O4 + [M+H]+: 371.1714, found: 371.1712. HPLC: 96.59% (λ = 254nm, tR = 10.54min).
实施例24：化合物1-(2-(-甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(I-A24)(IHCH-5223)的制备
Example 24: Compound 1-(2-(-methoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1,3-di Preparation of Hydrogen-2H-Benzo[d]imidazol-2-one(I-A24)(IHCH-5223)
将LRQ-04-153(50mg，0.25mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg，1.48mmol)，1-(2-溴乙基)-1,3-二氢-2H-苯并咪唑-2-酮(92mg，0.38mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(35mg，收率42％)。1H NMR(800MHz,CDCl3)δ9.72(s,1H),7.13(t,J＝7.8Hz,1H),7.10–7.06(m,2H),7.06–7.03(m,2H),7.03–7.00(m,1H),6.76(d,J＝7.9Hz,1H),4.12(t,J＝6.9Hz,2H),3.99(s,3H),3.83(s,2H),3.04–2.92(m,4H),2.77–2.68(m,2H).13C NMR(201MHz,CDCl3)δ155.57,149.30,145.29,143.72,130.41,129.75,128.07,123.34,121.68,121.48,111.96,111.34,109.80,107.97,106.07,56.16,54.67,50.52,50.36,39.17,20.90.HRMS(ESI)C21H22N3O3 +[M+H]+计算值：364.1656，实测值：364.1657。HPLC:95.01％(λ＝254nm,tR＝11.84min)。After dissolving LRQ-04-153 (50mg, 0.25mmol) in DMF (8mL), add DIPEA (191mg, 1.48mmol), 1-(2-bromoethyl)-1,3-dihydro-2H-benzene Imidazol-2-one (92mg, 0.38mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (35 mg, yield 42%). 1 H NMR (800MHz, CDCl 3 )δ9.72(s,1H),7.13(t,J=7.8Hz,1H),7.10–7.06(m,2H),7.06–7.03(m,2H),7.03– 7.00(m,1H),6.76(d,J=7.9Hz,1H),4.12(t,J=6.9Hz,2H),3.99(s,3H),3.83(s,2H),3.04–2.92(m ,4H),2.77–2.68(m,2H). 13 C NMR(201MHz,CDCl 3 )δ155.57,149.30,145.29,143.72,130.41,129.75,128.07,123.34,121.68,121.48,111.96,111. 34,109.80,107.97, 106.07, 56.16, 54.67, 50.52 , 50.36 , 39.17, 20.90 . HRMS ( ESI) Calcd. for C21H22N3O3 + [M+H]+: 364.1656, found: 364.1657. HPLC: 95.01% (λ=254nm, tR =11.84min).
实施例25：化合物7-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)喹啉-2(1H)-酮(I-A25)(IHCH-5225)的制备
Example 25: Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)quinoline-2( Preparation of 1H)-ketone (I-A25) (IHCH-5225)
将LRQ-05-137(22mg，0.10mmol)溶于DMF(8mL)后，依次加入DIPEA(84mg，0.65mmol)，LRQ-06-98(45mg，0.16mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(10mg，收率23％)。1H NMR(800MHz,CDCl3)δ12.06(s,1H),7.74(d,J＝9.4Hz,1H),7.48–7.42(m,1H),7.26(s,1H),7.09(t,J＝7.8Hz,1H),7.05–7.02(m,1H),7.00(d,J＝7.6Hz,1H),6.77–6.71(m,1H),6.62(d,J＝9.4Hz,1H),4.22(q,J＝7.0Hz,2H),3.78(s,2H),2.98–2.89(m,2H),2.79–2.67(m,6H),1.75–1.67(m,4H),1.48(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.55,145.86,144.55,143.97,142.25,140.93,138.77,129.63,127.80,123.63,123.36,120.43,118.26,115.53,111.81,111.18,107.27,64.51,57.04,50.50,49.95,35.85,29.00,26.63,20.47,15.03.HRMS(ESI)C26H29N2O3 +[M+H]+计算值：417.2173，实测值：417.2177。HPLC:98.08％(λ＝254nm,tR＝11.69min)。After LRQ-05-137 (22 mg, 0.10 mmol) was dissolved in DMF (8 mL), DIPEA (84 mg, 0.65 mmol) and LRQ-06-98 (45 mg, 0.16 mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (10 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 )δ12.06(s,1H),7.74(d,J＝9.4Hz,1H),7.48–7.42(m,1H),7.26(s,1H),7.09(t, J=7.8Hz,1H),7.05–7.02(m,1H),7.00(d,J=7.6Hz,1H),6.77–6.71(m,1H),6.62(d,J=9.4Hz,1H), 4.22(q,J=7.0Hz,2H),3.78(s,2H),2.98–2.89(m,2H),2.79–2.67(m,6H),1.75–1.67(m,4H),1.48(t, J＝7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ164.55, 145.86, 144.55, 143.97, 142.25, 140.93, 138.77, 129.63, 127.80, 123.63, 123.36, 120.43, 118.26, 1 15.53, 111.81, 111.18, 107.27 , 64.51, 57.04, 50.50, 49.95, 35.85, 29.00, 26.63, 20.47, 15.03. HRMS (ESI) Calculated for C 26 H 29 N 2 O 3 + [M+H]+: 417.2173, Found: 417.2177. HPLC: 98.08% (λ=254nm, tR =11.69min).
实施例26：化合物7-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙基)喹啉-2(1H)-酮(I-A26)(IHCH-5218)的制备
Example 26: Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)quinoline-2( Preparation of 1H)-ketone (I-A26) (IHCH-5218)
步骤1，将3-氨基苯丙酸甲酯(1.00g，5.58mmol)溶于二氯甲烷(10mL)，降温至0℃后，依次加入吡啶(883mg，11.16mmol)和肉桂酰氯(1.39g，8.37mmol)，升温至室温反应过夜。反应完毕后，加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到无色油状液体LRQ-06-89，无需纯化直接投入下一步反应。HRMS(ESI)C19H20NO3 +[M+H]+计算值：310.1438，实测值：310.1438。Step 1, dissolve methyl 3-aminophenylpropionate (1.00g, 5.58mmol) in dichloromethane (10mL), cool down to 0°C, add pyridine (883mg, 11.16mmol) and cinnamoyl chloride (1.39g, 8.37mmol), warming up to room temperature and reacting overnight. After completion of the reaction, add saturated aqueous sodium bicarbonate solution (10mL) to dilute, extract with ethyl acetate (50mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a colorless oily liquid LRQ-06 -89, directly put into the next reaction without purification. HRMS (ESI) calcd for C19H20NO3 + [M+H]+: 310.1438 , found : 310.1438.
步骤2，将LRQ-06-89溶于氯苯(20mL)，氮气置换三次后加入三氯化铝(3.72g,27.90mmol)，升温至95℃反应3小时。反应完毕后，将反应液降温至0℃，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体LRQ-06-90(954mg，两步反应收率74％)。1H NMR(800MHz,CDCl3)δ7.82(d,J＝9.4Hz,1H),7.54(d,J＝8.0Hz,1H),7.27(s,1H),7.14–7.11(m,1H),6.70(d,J＝9.3Hz,1H),3.70(s,3H),2.83–2.77(m,2H),2.66(t,J＝7.4Hz,2H)HRMS(ESI)C13H14NO3 +[M+H]+计算值：232.0968，实测值：232.0966。Step 2: Dissolve LRQ-06-89 in chlorobenzene (20mL), replace with nitrogen three times, add aluminum trichloride (3.72g, 27.90mmol), heat up to 95°C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0°C, diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure. Chromatographic separation and purification (ethyl acetate/petroleum ether=1:1) gave LRQ-06-90 (954 mg, two-step reaction yield 74%) as a white solid. 1 H NMR (800MHz, CDCl 3 ) δ7.82(d, J=9.4Hz, 1H), 7.54(d, J=8.0Hz, 1H), 7.27(s, 1H), 7.14–7.11(m, 1H) ,6.70(d,J=9.3Hz,1H),3.70(s,3H),2.83–2.77(m,2H),2.66(t,J=7.4Hz,2H) HRMS(ESI)C 13 H 14 NO 3 + [M+H]+ Calculated value: 232.0968, measured value: 232.0966.
步骤3，将LRQ-06-90(520mg，2.25mmol)溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(7mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色固体LRQ-06-91，无需纯化直接投入下一步反应。HRMS(ESI)C12H14NO2 +[M+H]+计算值：204.1019，实测值：204.1024。Step 3, LRQ-06-90 (520mg, 2.25mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (7mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-91, directly put into the next reaction without purification. HRMS (ESI) calcd for C12H14NO2 + [M+H] + : 204.1019 , found : 204.1024.
步骤4，将LRQ-06-91溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.12g,3.38mmol)和三苯基膦(1.18g,4.50mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到白色固体LRQ-06-92(370mg，两步反应收率62％)。1H NMR(600MHz,CDCl3)δ7.86(d,J＝9.3Hz,1H)7.58(d,J＝8.0Hz,1H),7.26(s,1H),7.14(d,J＝7.9Hz,1H),6.75(d,J＝9.3Hz,1H),3.41(t,J＝6.5Hz,2H),2.93–2.86(m,2H),2.23–2.20(m,2H).HRMS(ESI)C12H13BrNO+[M+H]+计算值：266.0175，实测值：266.0169。Step 4: Dissolve LRQ-06-91 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.12g, 3.38mmol) and triphenylphosphine (1.18g, 4.50mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:2), to obtain white solid LRQ-06-92 (370mg, two-step reaction yield 62%). 1 H NMR (600MHz, CDCl 3 ) δ7.86(d, J=9.3Hz, 1H) 7.58(d, J=8.0Hz, 1H), 7.26(s, 1H), 7.14(d, J=7.9Hz, 1H), 6.75(d, J=9.3Hz, 1H), 3.41(t, J=6.5Hz, 2H), 2.93–2.86(m, 2H), 2.23–2.20(m, 2H).HRMS(ESI)C 12 H 13 BrNO + [M+H]+ calcd: 266.0175, found: 266.0169.
步骤5，将LRQ-05-137(40mg，0.18mmol)溶于DMF(8mL)后，依次加入DIPEA(140mg，1.08mmol)，LRQ-06-92(72mg，0.27mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析 分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(22mg，收率30％)。1H NMR(800MHz,CDCl3)δ12.62(s,1H),7.78(d,J＝9.4Hz,1H),7.48(d,J＝8.0Hz,1H),7.28(s,1H),7.12–7.06(m,2H),7.03–7.00(m,1H),6.78–6.73(m,1H),6.68(d,J＝9.4Hz,1H),4.24(q,J＝7.0Hz,2H),3.69(s,2H),2.87–2.80(m,2H),2.80–2.77(m,2H),2.74–2.70(m,2H),2.66–2.59(m,2H),2.00–1.91(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.99,151.43,145.76,144.54,143.88,140.99,138.84,129.93,127.81,123.66,123.22,120.42,118.33,115.73,111.88,111.16,107.10,64.50,56.68,50.52,50.28,33.70,29.02,21.01,15.06.HRMS(ESI)C25H27N2O3 +[M+H]+计算值：403.2016，实测值：403.2017。HPLC:97.83％(λ＝254nm,tR＝11.70min)。Step 5, after dissolving LRQ-05-137 (40mg, 0.18mmol) in DMF (8mL), add DIPEA (140mg, 1.08mmol) and LRQ-06-92 (72mg, 0.27mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10mL), extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography. Separation and purification (methanol/dichloromethane=1:10) gave a pale yellow solid (22 mg, yield 30%). 1 H NMR (800MHz, CDCl 3 ) δ12.62(s, 1H), 7.78(d, J=9.4Hz, 1H), 7.48(d, J=8.0Hz, 1H), 7.28(s, 1H), 7.12 –7.06(m,2H),7.03–7.00(m,1H),6.78–6.73(m,1H),6.68(d,J=9.4Hz,1H),4.24(q,J=7.0Hz,2H), 3.69(s,2H),2.87–2.80(m,2H),2.80–2.77(m,2H),2.74–2.70(m,2H),2.66–2.59(m,2H),2.00–1.91(m,2H ), 1.50 (t, J=7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ164.99, 151.43, 145.76, 144.54, 143.88, 140.99, 138.84, 129.93, 127.81, 123.66, 123.22, 120.4 2,118.33,115.73 ,111.88,111.16,107.10,64.50,56.68,50.52,50.28,33.70,29.02,21.01,15.06.HRMS(ESI)C 25 H 27 N 2 O 3 + [M+H]+ Calculated value: 403.2016, Measured value: 403.2017. HPLC: 97.83% (λ=254nm, tR =11.70min).
实施例27：化合物7-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)喹啉-2(1H)-酮(I-A27)(IHCH-5217)的制备
Example 27: Compound 7-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)quinoline-2( Preparation of 1H)-ketone (I-A27) (IHCH-5217)
步骤1，将3-氨基苯乙酸甲酯(1.00g，6.05mmol)溶于二氯甲烷(10mL)，降温至0℃后，依次加入吡啶(957mg，12.10mmol)和肉桂酰氯(1.52g，9.08mmol)，升温至室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到棕黄色油状液体LRQ-06-82，无需纯化直接投入下一步反应。HRMS(ESI)C18H18NO3 +[M+H]+计算值：296.1281，实测值：296.1288。Step 1, dissolve methyl 3-aminophenylacetic acid (1.00g, 6.05mmol) in dichloromethane (10mL), after cooling down to 0°C, add pyridine (957mg, 12.10mmol) and cinnamoyl chloride (1.52g, 9.08 mmol), warming up to room temperature and reacting overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10mL), extracted with ethyl acetate (50mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain brown-yellow oily liquid LRQ-06- 82, directly used in the next reaction without purification. HRMS (ESI) calcd for C18H18NO3 + [M+H]+: 296.1281, found : 296.1288.
步骤2，将LRQ-06-82溶于氯苯(20mL)，氮气置换三次后加入三氯化铝(4.03g,30.25mmol)，升温至95℃反应3小时。反应完毕后将反应液降温至0℃，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体LRQ-06-84(604mg，两步反应收率46％)。1H NMR(800MHz,CDCl3)δ7.81(d,J＝9.4Hz,1H),7.54(d,J＝8.0Hz,1H),7.32(s,1H),7.18–7.15(m,1H),6.71(d,J＝9.4Hz,1H),3.74(s,2H),3.71(s,3H).HRMS(ESI)C12H12NO3 +[M+H]+计算值：218.0812，实测值：218.0813。Step 2: Dissolve LRQ-06-82 in chlorobenzene (20mL), replace with nitrogen three times, add aluminum trichloride (4.03g, 30.25mmol), heat up to 95°C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0°C, diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure. After separation and purification (ethyl acetate/petroleum ether=1:1), LRQ-06-84 (604 mg, two-step reaction yield 46%) was obtained as a light yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ7.81(d, J=9.4Hz, 1H), 7.54(d, J=8.0Hz, 1H), 7.32(s, 1H), 7.18–7.15(m, 1H) ,6.71(d,J＝9.4Hz,1H),3.74(s,2H),3.71(s,3H).HRMS(ESI)C 12 H 12 NO 3 + [M+H]+ calculated value: 218.0812, measured Value: 218.0813.
步骤3，将LRQ-06-84(560mg，2.57mmol)溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(8mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色固体LRQ-06-85，无需纯化直接投入下一步反应。HRMS(ESI)C11H12NO2 +[M+H]+计算值：190.0863，实测值：190.0865。 Step 3, LRQ-06-84 (560mg, 2.57mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-85, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H12NO2 + [M+H]+: 190.0863, found : 190.0865 .
步骤4，将LRQ-06-85溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.28g,3.86mmol)和三苯基膦(1.35g,5.14mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到白色固体LRQ-06-86(300mg，两步反应收率46％)。1H NMR(600MHz,CDCl3)δ7.88(d,J＝9.4Hz,1H),7.58(d,J＝8.0Hz,1H),7.26(s,1H),7.16(d,J＝7.9Hz,1H),6.76(d,J＝9.4Hz,1H),3.63(t,J＝7.3Hz,2H),3.29(t,J＝7.3Hz,2H).HRMS(ESI)C11H11BrNO+[M+H]+计算值：252.0019，实测值：252.0013。Step 4: Dissolve LRQ-06-85 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.28g, 3.86mmol) and triphenylphosphine (1.35g, 5.14mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1) to obtain white solid LRQ-06-86 (300mg, two-step reaction yield 46%). 1 H NMR (600MHz, CDCl 3 ) δ7.88(d, J=9.4Hz, 1H), 7.58(d, J=8.0Hz, 1H), 7.26(s, 1H), 7.16(d, J=7.9Hz ,1H),6.76(d,J=9.4Hz,1H),3.63(t,J=7.3Hz,2H),3.29(t,J=7.3Hz,2H).HRMS(ESI)C 11 H 11 BrNO + [M+H]+ calculated value: 252.0019, measured value: 252.0013.
步骤5，将LRQ-05-137(40mg，0.18mmol)溶于DMF(8mL)后，依次加入DIPEA(140mg，1.08mmol)，LRQ-06-86(68mg，0.27mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(14mg，收率20％)。1H NMR(800MHz,CDCl3)δ12.20(s,1H),7.79–7.70(m,1H),7.46(d,J＝7.9Hz,1H),7.24(s,1H),7.11(t,J＝7.7Hz,2H),7.02(d,J＝7.7Hz,1H),6.76(d,J＝7.9Hz,1H),6.68–6.61(m,1H),4.25(q,J＝7.0Hz,2H),3.81(s,2H),3.04–2.97(m,2H),2.97–2.90(m,4H),2.79–2.73(m,2H),1.51(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.68,151.13,144.58,143.94,143.65,140.90,138.74,129.86,127.94,123.92,123.30,120.68,118.49,115.91,111.94,111.20,107.18,64.53,58.75,50.57,50.21,34.30,20.95,15.08.HRMS(ESI)C24H25N2O3 +[M+H]+计算值：389.1860，实测值：389.1865。HPLC:95.13％(λ＝254nm,tR＝11.68min)。Step 5, after dissolving LRQ-05-137 (40mg, 0.18mmol) in DMF (8mL), add DIPEA (140mg, 1.08mmol) and LRQ-06-86 (68mg, 0.27mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a light yellow solid (14 mg, yield 20%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ12.20(s, 1H), 7.79–7.70(m, 1H), 7.46(d, J=7.9Hz, 1H), 7.24(s, 1H), 7.11(t, J＝7.7Hz, 2H), 7.02(d, J＝7.7Hz, 1H), 6.76(d, J＝7.9Hz, 1H), 6.68–6.61(m, 1H), 4.25(q, J＝7.0Hz, 13 C NMR (201MHz, CDCl 3 )δ164.68, 151.13, 144.58, 143.94, 143.65, 140.90, 138.74, 129.86, 127.94, 123.92, 123.30, 120.68, 118.49, 115.91, 111.94, 1 11.20, 107.18, 64.53, 58.75, 50.57, 50.21, 34.30, 20.95 , 15.08. HRMS (ESI) Calcd. for C24H25N2O3 + [ M + H]+: 389.1860, found: 389.1865. HPLC: 95.13% (λ=254nm, tR =11.68min).
实施例28：化合物1-((8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)环己烷-1-醇(I-A28)(IHCH-5232)的制备
Example 28: Compound 1-((8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)methyl)cyclohexane-1-ol Preparation of (I-A28)(IHCH-5232)
将LRQ-05-137(50mg,0.23mmol)溶于无水乙醇(10mL)，加入亚甲基环己烷氧化物(128mg,1.15mmol)后，升温至60℃反应过夜。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(29mg，收率38％)。1H NMR(800MHz,CDCl3)δ7.12(t,J＝7.8Hz,1H),7.03(d,J＝7.7Hz,1H),6.79–6.75(m,1H),4.25(q,J＝7.0Hz,2H),3.87(s,2H),3.06–2.94(m,2H),2.76–2.68(m,2H),2.56(s,2H),1.71–1.63(m,2H),1.63–1.53(m,3H),1.51(t,J＝7.0Hz,3H),1.49–1.42(m,2H),1.39–1.34(m,2H),1.30–1.23(m,1H).13C NMR(201MHz,CDCl3)δ148.08,144.63,143.82,129.85,123.36,112.07,111.15,107.18,70.72,64.53,55.72,52.85,52.82,36.63(2C),26.02,22.28(2C),21.97,15.07.HRMS(ESI)C20H28NO3 +[M+H]+计算值：330.2064，实测值：330.2069。HPLC:97.60％(λ＝254nm,tR＝11.58min)。 LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in absolute ethanol (10 mL), methylenecyclohexane oxide (128 mg, 1.15 mmol) was added, and the temperature was raised to 60° C. to react overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain a white solid (29 mg, yield 38%). 1 H NMR (800MHz, CDCl 3 ) δ7.12(t, J=7.8Hz, 1H), 7.03(d, J=7.7Hz, 1H), 6.79–6.75(m, 1H), 4.25(q, J= 7.0Hz, 2H), 3.87(s, 2H), 3.06–2.94(m, 2H), 2.76–2.68(m, 2H), 2.56(s, 2H), 1.71–1.63(m, 2H), 1.63–1.53 (m,3H),1.51(t,J＝7.0Hz,3H),1.49–1.42(m,2H),1.39–1.34(m,2H),1.30–1.23(m,1H). 13 C NMR(201MHz , CDCl 3 )δ148.08, 144.63, 143.82, 129.85, 123.36, 112.07, 111.15, 107.18, 70.72, 64.53, 55.72, 52.85, 52.82, 36.63(2C), 26.02, 22.28(2C), 2 1.97, 15.07. HRMS (ESI) Calcd . for C20H28NO3 + [M+H] + : 330.2064 , found: 330.2069. HPLC: 97.60% (λ=254nm, tR =11.58min).
实施例29：化合物7-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-1,8-萘啶-2(1H)-酮(I-A29)(IHCH-5213)的制备
Example 29: Compound 7-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-1,8 - Preparation of naphthyridin-2(1H)-one (I-A29) (IHCH-5213)
步骤1，将浓硫酸(6mL)降温至0℃后，依次加入2-氨基-7-羟基-1,8-萘啶(1.00g，6.21mmol)和亚硝酸钠(684mg，9.92mmol)，反应15分钟后升温至室温继续反应15分钟。反应完毕后倒入冰水中，加饱和碳酸氢钠水溶液调节pH至8，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到灰棕色固体LRQ-06-64，无需纯化直接投入下一步反应。HRMS(ESI)C8H7N2O2 +[M+H]+计算值：163.0502，实测值：163.0507。Step 1, after cooling concentrated sulfuric acid (6mL) to 0°C, add 2-amino-7-hydroxyl-1,8-naphthyridine (1.00g, 6.21mmol) and sodium nitrite (684mg, 9.92mmol) successively, and react After 15 minutes, the temperature was raised to room temperature and the reaction was continued for 15 minutes. After the reaction was completed, pour it into ice water, add saturated aqueous sodium bicarbonate solution to adjust the pH to 8, extract with ethyl acetate (50mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a gray-brown solid LRQ-06-64, directly put into the next reaction without purification. HRMS (ESI) calcd for C8H7N2O2 + [M+H]+: 163.0502, found : 163.0507.
步骤2，将LRQ-06-64溶于DMF(20mL)后，依次加入K2CO3(858mg，6.21mmol)，1,4-二溴丁烷(2.68g，12.42mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到红棕色固体LRQ-06-65(202mg，两步反应收率11％)。1H NMR(800MHz,CDCl3)δ10.09(s,1H),7.72(d,J＝8.4Hz,1H),7.64(d,J＝9.4Hz,1H),6.59(d,J＝8.4Hz,1H),6.55(d,J＝9.4Hz,1H),4.41(t,J＝6.3Hz,2H),3.49(t,J＝6.7Hz,2H),2.09–2.01(m,2H),1.99–1.92(m,2H).HRMS(ESI)C12H14BrN2O2 +[M+H]+计算值：297.0233，实测值：297.0237。Step 2, after dissolving LRQ-06-64 in DMF (20mL), add K 2 CO 3 (858mg, 6.21mmol) and 1,4-dibromobutane (2.68g, 12.42mmol) sequentially, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:2) to obtain LRQ-06-65 (202 mg, two-step reaction yield 11%) as a reddish-brown solid. 1 H NMR (800MHz, CDCl 3 ) δ10.09(s, 1H), 7.72(d, J=8.4Hz, 1H), 7.64(d, J=9.4Hz, 1H), 6.59(d, J=8.4Hz ,1H),6.55(d,J=9.4Hz,1H),4.41(t,J=6.3Hz,2H),3.49(t,J=6.7Hz,2H),2.09–2.01(m,2H),1.99 -1.92 (m, 2H ). HRMS (ESI) Calcd. for C12H14BrN2O2 + [M+H]+: 297.0233 , found : 297.0237.
步骤3，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-65(104mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(10mg，收率10％)。1H NMR(800MHz,CDCl3)δ9.82(s,1H),7.69(d,J＝8.4Hz,1H),7.61(d,J＝9.4Hz,1H),7.10(t,J＝7.8Hz,1H),7.01(d,J＝7.6Hz,1H),6.77–6.73(m,1H),6.58(d,J＝8.4Hz,1H),6.52(d,J＝9.4Hz,1H),4.43–4.36(m,2H),4.24(q,J＝7.0Hz,2H),3.72(s,2H),2.92–2.84(m,2H),2.75–2.71(m,2H),2.71–2.65(m,2H),1.91–1.82(m,2H),1.82–1.75(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.86,163.87,151.28,148.53,144.55,143.89,139.31,138.45,129.87,123.27,119.18,111.85,111.17,108.77,107.52,107.11,66.69,64.51,57.06,50.54,50.19,26.87,24.02,20.90,15.07.HRMS(ESI)C25H28N3O4 +[M+H]+计算值：434.2074，实测值：434.2071。HPLC:95.39％(λ＝254nm,tR＝12.05min)。Step 3, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-06-65 (104mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (10 mg, yield 10%). 1 H NMR (800MHz, CDCl 3 ) δ9.82(s, 1H), 7.69(d, J=8.4Hz, 1H), 7.61(d, J=9.4Hz, 1H), 7.10(t, J=7.8Hz ,1H),7.01(d,J=7.6Hz,1H),6.77–6.73(m,1H),6.58(d,J=8.4Hz,1H),6.52(d,J=9.4Hz,1H),4.43 –4.36(m,2H),4.24(q,J＝7.0Hz,2H),3.72(s,2H),2.92–2.84(m,2H),2.75–2.71(m,2H),2.71–2.65(m ,2H),1.91–1.82(m,2H),1.82–1.75(m,2H),1.50(t,J＝7.0Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ164.86,163.87,151.28,148.53 ,144.55,143.89,139.31,138.45,129.87,123.27,119.18,111.85,111.17,108.77,107.52,107.11,66.69,64.51,57.06,50.54,50.19,26.87, 24.02, 20.90, 15.07. HRMS (ESI) C 25 H 28 N 3 O 4 + [M+H]+ calcd: 434.2074, found: 434.2071. HPLC: 95.39% (λ=254nm, tR =12.05min).
实施例30：化合物6-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁氧基)-2H-苯并[b][1,4] 恶嗪-3(4H)-酮(I-A30)(IHCH-5194)的制备
Example 30: Compound 6-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butoxy)-2H-benzene and[b][1,4] Preparation of Oxazin-3(4H)-one(I-A30)(IHCH-5194)
步骤1，将6-羟基-2H-1,4-苯并嗪-3(4H)-酮(0.3g，1.77mmol)溶于DMF(10mL)后，依次加入K2CO3(0.25g，1.77mmol)，1,4-二溴丁烷(1.15g，5.31mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到黄色固体LRQ-05-61(0.20g，收率38％)。1H NMR(800MHz,CDCl3)δ7.72(s,1H),6.89(d,J＝8.8Hz,1H),6.53–6.46(m,1H),6.37–6.32(m,1H),4.56(s,2H),3.94(t,J＝6.1Hz,2H),3.48(t,J＝6.6Hz,2H),2.09–2.01(m,2H),1.96–1.88(m,2H).HRMS(ESI)C12H15BrNO3 +[M+H]+计算值：300.0230，实测值：300.0233。Step 1, after dissolving 6-hydroxy-2H-1,4-benzoxazin-3(4H)-one (0.3g, 1.77mmol) in DMF (10mL), add K 2 CO 3 (0.25g, 1.77 mmol), 1,4-dibromobutane (1.15g, 5.31mmol), react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:2) to obtain a yellow solid LRQ-05-61 (0.20 g, yield 38%). 1 H NMR (800MHz, CDCl 3 ) δ7.72(s, 1H), 6.89(d, J=8.8Hz, 1H), 6.53–6.46(m, 1H), 6.37–6.32(m, 1H), 4.56( s,2H),3.94(t,J＝6.1Hz,2H),3.48(t,J＝6.6Hz,2H),2.09–2.01(m,2H),1.96–1.88(m,2H).HRMS(ESI ) Calcd. for C12H15BrNO3 + [M+H]+: 300.0230, found: 300.0233 .
步骤2，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-05-61(105mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到橙色固体(31mg，收率31％)。1H NMR(800MHz,CDCl3)δ8.62(s,1H),7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.86(d,J＝8.8Hz,1H),6.78–6.74(m,1H),6.51–6.47(m,1H),6.37(d,J＝2.6Hz,1H),4.54(s,2H),4.25(q,J＝6.9Hz,2H),3.97–3.89(m,2H),3.73(s,2H),2.92–2.84(m,2H),2.76–2.72(m,2H),2.72–2.65(m,2H),1.87–1.81(m,2H),1.81–1.75(m,2H),1.51(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ166.46,154.82,151.21,144.59,143.94,137.71,129.85,126.94,123.33,117.32,111.88,111.18,109.53,107.19,102.92,68.41,67.57,64.55,57.00,50.53,50.17,27.22,23.97,20.84,15.07.HRMS(ESI)C25H29N2O5 +[M+H]+计算值：437.2071，实测值：437.2072。HPLC:96.67％(λ＝254nm,tR＝11.92min)。Step 2, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-05-61 (105mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), an orange solid (31 mg, yield 31%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ8.62(s, 1H), 7.11(t, J=7.8Hz, 1H), 7.02(d, J=7.7Hz, 1H), 6.86(d, J=8.8Hz ,1H),6.78–6.74(m,1H),6.51–6.47(m,1H),6.37(d,J＝2.6Hz,1H),4.54(s,2H),4.25(q,J＝6.9Hz, 2H),3.97–3.89(m,2H),3.73(s,2H),2.92–2.84(m,2H),2.76–2.72(m,2H),2.72–2.65(m,2H),1.87–1.81( m,2H),1.81–1.75(m,2H),1.51(t,J=7.0Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ166.46,154.82,151.21,144.59,143.94,137.71,129.85,126.94 25H 29 N 2 O 5 + [M +H]+ calculated value: 437.2071, measured value: 437.2072. HPLC: 96.67% (λ=254nm, tR =11.92min).
实施例31：化合物2-(3-(苯并[d][1,3]二氧-5-基氧基)丙基)-8-乙氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶(I-A31)(IHCH-5193)的制备
Example 31: Compound 2-(3-(Benzo[d][1,3]diox-5-yloxy)propyl)-8-ethoxy-1,2,3,4-tetrahydro Preparation of Benzofuro[2,3-c]pyridine(I-A31)(IHCH-5193)
步骤1，将芝麻酚(1.00g，7.23mmol)溶于DMF(10mL)后，依次加入K2CO3(1.00g，7.23mmol)，1,3-二溴丙烷(4.39g，21.72mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层 析分离纯化(乙酸乙酯/石油醚＝1:10)，得到黄色固体LRQ-05-51(0.80g，收率43％)。1H NMR(800MHz,CDCl3)δ6.70(d,J＝8.4Hz,1H),6.51–6.49(m,1H),6.35–6.31(m,1H),5.92(s,2H),4.03(t,J＝5.8Hz,2H),3.62–3.55(m,2H),2.31–2.24(m,2H).HRMS(ESI)C10H12BrO3 +[M+H]+计算值：258.9964，实测值：258.9970。Step 1, after dissolving sesamol (1.00g, 7.23mmol) in DMF (10mL), adding K 2 CO 3 (1.00g, 7.23mmol), 1,3-dibromopropane (4.39g, 21.72mmol) in sequence, React overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was purified by silica gel column layer Analysis, separation and purification (ethyl acetate/petroleum ether=1:10) gave LRQ-05-51 as a yellow solid (0.80 g, yield 43%). 1 H NMR (800MHz, CDCl 3 ) δ6.70(d, J=8.4Hz, 1H), 6.51–6.49(m, 1H), 6.35–6.31(m, 1H), 5.92(s, 2H), 4.03( t,J＝5.8Hz,2H),3.62–3.55(m,2H),2.31–2.24(m,2H).HRMS(ESI)C 10 H 12 BrO 3 + [M+H]+Calculated value: 258.9964, Measured value: 258.9970.
步骤2，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-05-51(90mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(39mg，收率42％)。1H NMR(800MHz,CDCl3)δ7.15–7.09(m,1H),7.04–7.00(m,1H),6.76(d,J＝7.9Hz,1H),6.72–6.67(m,1H),6.52–6.48(m,1H),6.36–6.30(m,1H),5.90(s,2H),4.25(q,J＝7.0Hz,2H),4.03–3.95(m,2H),3.73(s,2H),2.91–2.83(m,2H),2.83–2.76(m,2H),2.76–2.70(m,2H),2.08–1.99(m,2H),1.51(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ154.59,151.31,148.33,144.56,143.91,141.68,129.89,123.25,111.87,111.16,108.03,107.13,105.79,101.19,98.21,67.07,64.51,54.13,50.56,50.34,27.49,20.95,15.06.HRMS(ESI)C23H26NO5 +[M+H]+计算值：396.1805，实测值：396.1800。HPLC:97.98％(λ＝254nm,tR＝12.72min)。Step 2, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-05-51 (90mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a white solid (39 mg, yield 42%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.15–7.09(m,1H),7.04–7.00(m,1H),6.76(d,J=7.9Hz,1H),6.72–6.67(m,1H), 6.52–6.48(m,1H),6.36–6.30(m,1H),5.90(s,2H),4.25(q,J＝7.0Hz,2H),4.03–3.95(m,2H),3.73(s, 2H),2.91–2.83(m,2H),2.83–2.76(m,2H),2.76–2.70(m,2H),2.08–1.99(m,2H),1.51(t,J＝7.0Hz,3H) . 13 C NMR (201MHz, CDCl 3 ) δ154.59, 151.31, 148.33, 144.56, 143.91, 141.68, 129.89, 123.25, 111.87, 111.16, 108.03, 107.13, 105.79, 101.19, 98. 21,67.07,64.51,54.13,50.56,50.34, 27.49, 20.95, 15.06. HRMS ( ESI ) Calcd. for C23H26NO5 + [M+H]+: 396.1805 , found: 396.1800. HPLC: 97.98% (λ=254nm, tR =12.72min).
实施例32：化合物N-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环庚烷甲酰胺(I-A32)(IHCH-5215)的制备
Example 32: Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cycloheptanecarboxamide Preparation of (I-A32)(IHCH-5215)
将LRQ-06-67(70mg,0.19mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(150mg,1.16mmol)和环庚烷甲酰氯(46mg,0.28mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体(35mg，收率47％)。1H NMR(800MHz,CDCl3)δ7.13(t,J＝7.8Hz,1H),7.05–7.02(m,1H),6.80–6.75(m,1H),6.11(s,1H),4.25(q,J＝7.0Hz,2H),3.74(s,2H),3.46–3.39(m,2H),2.93–2.85(m,2H),2.80–2.76(m,2H),2.76–2.71(m,2H),2.25–2.18(m,1H),1.89–1.83(m,2H),1.78–1.71(m,2H),1.68–1.62(m,2H),1.58–1.49(m,7H),1.46–1.40(m,2H).13C NMR(201MHz,CDCl3)δ177.64,152.38,144.64,143.95,129.69,123.46,111.92,111.17,107.32,64.57,55.61,50.15,50.06,47.56,36.35,31.83(2C),28.24(2C),26.72(2C),20.74,15.07.HRMS(ESI)C23H33N2O3 +[M+H]+计算值：385.2486，实测值：385.2487。HPLC:96.48％(λ＝254nm,tR＝13.09min)。LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and cycloheptanecarbonyl chloride (46mg, 0.28mmol), and reacted at room temperature overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a light yellow solid (35 mg, yield 47%). 1 H NMR (800MHz, CDCl 3 ) δ7.13(t, J=7.8Hz, 1H), 7.05–7.02(m, 1H), 6.80–6.75(m, 1H), 6.11(s, 1H), 4.25( q,J＝7.0Hz,2H),3.74(s,2H),3.46–3.39(m,2H),2.93–2.85(m,2H),2.80–2.76(m,2H),2.76–2.71(m, 2H),2.25–2.18(m,1H),1.89–1.83(m,2H),1.78–1.71(m,2H),1.68–1.62(m,2H),1.58–1.49(m,7H),1.46– 1.40(m,2H) .13C NMR(201MHz,CDCl 3 )δ177.64,152.38,144.64,143.95,129.69,123.46,111.92,111.17,107.32,64.57,55.61,50.15,50.06,47.5 6,36.35,31.83(2C) , 28.24(2C), 26.72(2C), 20.74 , 15.07. HRMS (ESI) Calcd . for C23H33N2O3 + [M+H] + : 385.2486 , found: 385.2487. HPLC: 96.48% (λ=254nm, tR =13.09min).
实施例33：化合物N-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环戊烷甲酰胺(I- A33)(IHCH-5214)的制备
Example 33: Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cyclopentanecarboxamide (I- A33) Preparation of (IHCH-5214)
将LRQ-06-67(70mg,0.19mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(150mg,1.16mmol)和环戊基甲酰氯(40mg,0.28mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体(20mg，收率29％)。1H NMR(800MHz,CDCl3)δ7.12(t,J＝7.8Hz,1H),7.02(d,J＝7.4Hz,1H),6.79–6.74(m,1H),6.18(s,1H),4.24(q,J＝7.0Hz,2H),3.71(s,2H),3.47–3.40(m,2H),2.90–2.84(m,2H),2.78–2.73(m,2H),2.73–2.68(m,2H),2.54–2.46(m,1H),1.87–1.79(m,2H),1.77–1.67(m,4H),1.59–1.52(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ176.56,150.83,144.59,143.89,129.70,123.38,111.88,111.13,107.25,64.53,55.56,50.12,50.01,45.94,36.51,30.58(2C),25.99(2C),20.77,15.03.HRMS(ESI)C21H29N2O3 +[M+H]+计算值：357.2173，实测值：357.2170。HPLC:96.44％(λ＝254nm,tR＝12.37min)。LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and cyclopentylformyl chloride (40mg, 0.28mmol), and reacted at room temperature overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a light yellow solid (20 mg, yield 29%). 1 H NMR (800MHz, CDCl 3 ) δ7.12(t, J=7.8Hz, 1H), 7.02(d, J=7.4Hz, 1H), 6.79–6.74(m, 1H), 6.18(s, 1H) ,4.24(q,J＝7.0Hz,2H),3.71(s,2H),3.47–3.40(m,2H),2.90–2.84(m,2H),2.78–2.73(m,2H),2.73–2.68 (m,2H),2.54–2.46(m,1H),1.87–1.79(m,2H),1.77–1.67(m,4H),1.59–1.52(m,2H),1.50(t,J＝7.0Hz ,3H). 13 C NMR (201MHz, CDCl 3 ) δ176.56, 150.83, 144.59, 143.89, 129.70, 123.38, 111.88, 111.13, 107.25, 64.53, 55.56, 50.12, 50.01, 45.94, 36.5 1,30.58(2C),25.99( 2C), 20.77 , 15.03 . HRMS ( ESI ) calcd for C21H29N2O3 + [M+H] + : 357.2173, found: 357.2170. HPLC: 96.44% (λ=254nm, tR =12.37min).
实施例34：化合物3-(3-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)环丁基)-1,1-二甲基脲(I-A34)(IHCH-5195)的制备
Example 34: Compound 3-(3-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)cyclobutane base)-1,1-dimethylurea (I-A34) (IHCH-5195)
步骤1，将3-氧代环丁基氨基甲酸叔丁酯(2.00g，10.80mmol)溶于DCM(10mL)后，加入甲氧甲酰基亚甲基三苯基膦(4.33g，12.96mmol)，室温下反应过夜。反应完毕后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-05-148(2.22g，收率85％)。1H NMR(600MHz,CDCl3)δ5.70(s,1H),4.81(s,1H),4.31–4.15(m,1H),3.69(s,3H),3.62–3.47(m,1H),3.26–3.11(m,1H),3.00–2.84(m,1H),2.79–2.65(m,1H),1.45(s,9H).HRMS(ESI)C12H20NO4 +[M+H]+计算值：242.1387，实测值：242.1384。 Step 1, After dissolving tert-butyl 3-oxocyclobutylcarbamate (2.00g, 10.80mmol) in DCM (10mL), add methoxymethylenetriphenylphosphine (4.33g, 12.96mmol) , react overnight at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:4) to obtain LRQ-05-148 (2.22 g, yield 85%) as a yellow solid. 1 H NMR (600MHz, CDCl 3 )δ5.70(s,1H),4.81(s,1H),4.31–4.15(m,1H),3.69(s,3H),3.62–3.47(m,1H), 3.26–3.11(m,1H),3.00–2.84(m,1H),2.79–2.65(m,1H),1.45(s,9H).HRMS(ESI)C 12 H 20 NO 4 + [M+H] + Calculated: 242.1387, Measured: 242.1384.
步骤2，将LRQ-05-148(2.00g，8.30mmol)溶于无水甲醇(20mL)后，加入10％钯炭，氢气置换三次，通入氢气，室温下反应过夜。反应完毕后过滤，减压蒸除溶剂，得到白色固体LRQ-05-149，无需纯化直接投入下一步反应。HRMS(ESI)C12H22NO4 +[M+H]+计算值：244.1543，实测值：244.1546。Step 2, after dissolving LRQ-05-148 (2.00 g, 8.30 mmol) in anhydrous methanol (20 mL), add 10% palladium carbon, replace with hydrogen three times, pass in hydrogen, and react overnight at room temperature. After the reaction was completed, it was filtered, and the solvent was evaporated under reduced pressure to obtain a white solid LRQ-05-149, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C12H22NO4 + [M+H]+: 244.1543 , found : 244.1546.
步骤3，将LRQ-05-149溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(25mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-05-150，无需纯化直接投入下一步反应。HRMS(ESI)C11H12NO3 +[M+H]+计算值：216.1594，实测值：216.1589。Step 3: Dissolve LRQ-05-149 in THF (20 mL), replace with nitrogen three times and cool the reaction solution to -10°C, add DIBAL-H (25 mL, 1.0 M THF solution). Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-05-150, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H12NO3 + [M+H]+: 216.1594 , found : 216.1589.
步骤4，将LRQ-05-150溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(2.79g,8.41mmol)和三苯基膦(2.94g,11.21mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯)，得到白色固体LRQ-06-03(1.38g，三步反应收率60％)。1H NMR(600MHz,CDCl3)δ4.25–4.07(m,1H),3.36–3.27(m,2H),2.56–1.86(m,7H),1.44–1.39(m,9H).HRMS(ESI)C11H20BrNO2Na+[M+H]+计算值：300.0570，实测值：300.0575。Step 4: Dissolve LRQ-05-150 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (2.79g, 8.41mmol) and triphenylphosphine (2.94g, 11.21mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate) , to obtain white solid LRQ-06-03 (1.38g, three-step reaction yield 60%). 1 H NMR (600MHz, CDCl 3 ) δ4.25–4.07(m,1H),3.36–3.27(m,2H),2.56–1.86(m,7H),1.44–1.39(m,9H).HRMS(ESI ) Calcd. for C11H20BrNO2Na + [M+H]+: 300.0570, found : 300.0575.
步骤5，将LRQ-06-03(250mg,1.41mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂得到淡黄色油状液体LRQ-06-03-NH2，无需纯化直接投入下一步反应。HRMS(ESI)C6H13BrN+[M+H]+计算值：178.0226，实测值：178.0227。Step 5, LRQ-06-03 (250mg, 1.41mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a light yellow oily liquid LRQ-06-03-NH2, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C6H13BrN + [M+H]+: 178.0226, found: 178.0227 .
步骤6，将LRQ-06-03-NH2溶于DCM(10mL)后，依次加入三乙胺(428mg,4.23mmol)和二甲氨基甲酰氯(182mg,1.69mmol)，室温反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色油状液体LRQ-06-04(132mg，两步反应收率59％)。1H NMR(600MHz,CDCl3)δ4.23–4.07(m,1H),3.39–3.24(m,2H),2.94–2.83(m,6H),2.61–1.90(m,7H).HRMS(ESI)C9H18BrN2O+[M+H]+计算值：249.0597，实测值：249.0600。Step 6, after dissolving LRQ-06-03-NH2 in DCM (10mL), triethylamine (428mg, 4.23mmol) and dimethylcarbamoyl chloride (182mg, 1.69mmol) were added successively, and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (Ethyl acetate/petroleum ether=1:1) to obtain light yellow oily liquid LRQ-06-04 (132mg, two-step reaction yield 59%). 1 H NMR (600MHz, CDCl 3 ) δ4.23–4.07(m,1H),3.39–3.24(m,2H),2.94–2.83(m,6H),2.61–1.90(m,7H).HRMS(ESI ) Calcd. for C 9 H 18 BrN 2 O + [M+H]+: 249.0597, found: 249.0600.
步骤7，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-04(87mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到橙色固体(38mg，收率42％)。1H NMR(800MHz,CDCl3)δ7.12–7.08(m,1H),7.01(d,J＝7.7Hz,1H),6.75(d,J＝7.9Hz,1H),4.52–4.40(m,1H),4.26–4.21(m,2H),3.69(s,2H),2.89–2.86(m,6H),2.86–2.82(m,2H),2.74–2.69(m,2H),2.54–2.51(m,2H),2.35–1.60(m,7H),1.50(t,J＝7.0Hz,3H).HRMS(ESI)C22H32N3O3 +[M+H]+计算值：386.2438，实测值：386.2431。HPLC:95.46％(λ＝254nm,tR＝11.55min)。Step 7, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-06-04 (87mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), an orange solid (38 mg, yield 42%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.12–7.08(m, 1H), 7.01(d, J=7.7Hz, 1H), 6.75(d, J=7.9Hz, 1H), 4.52–4.40(m, 1H),4.26–4.21(m,2H),3.69(s,2H),2.89–2.86(m,6H),2.86–2.82(m,2H),2.74–2.69(m,2H),2.54–2.51( m,2H),2.35–1.60(m,7H),1.50(t,J＝7.0Hz,3H).HRMS(ESI)C 22 H 32 N 3 O 3 + [M+H]+ calculated value: 386.2438, Measured value: 386.2431. HPLC: 95.46% (λ=254nm, tR =11.55min).
实施例35：化合物N-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯甲酰胺(I-A35) (IHCH-5212)的制备
Example 35: Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)benzamide (I -A35) Preparation of (IHCH-5212)
将LRQ-06-67(70mg,0.19mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(150mg,1.16mmol)和苯甲酰氯(40mg,0.28mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体(10mg，收率14％)。1H NMR(800MHz,MeOH-d4)δ8.31(s,1H),7.88–7.80(m,2H),7.51(t,J＝7.4Hz,1H),7.47–7.39(m,2H),7.11(t,J＝7.8Hz,1H),7.03(d,J＝7.7Hz,1H),6.85–6.79(m,1H),4.20(q,J＝7.0Hz,2H),3.93(s,2H),3.72–3.63(m,2H),3.12–3.06(m,2H),3.04–2.98(m,2H),2.83–2.75(m,2H),1.43(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ170.41,150.46,145.88,145.45,135.38,132.75,130.57,129.55(2C),128.29(2C),124.62,112.80,112.15,109.11,65.63,57.18,51.56,50.74,38.01,21.03,15.26.HRMS(ESI)C22H25N2O3 +[M+H]+计算值：365.1860，实测值：365.1863。HPLC:96.03％(λ＝254nm,tR＝12.20min)。LRQ-06-67 (70mg, 0.19mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), added DIPEA (150 mg, 1.16 mmol) and benzoyl chloride (40 mg, 0.28 mmol), and reacted overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a light yellow solid (10 mg, yield 14%). 1 H NMR (800MHz, MeOH-d 4 )δ8.31(s,1H),7.88–7.80(m,2H),7.51(t,J＝7.4Hz,1H),7.47–7.39(m,2H), 7.11(t, J=7.8Hz, 1H), 7.03(d, J=7.7Hz, 1H), 6.85–6.79(m, 1H), 4.20(q, J=7.0Hz, 2H), 3.93(s, 2H ),3.72–3.63(m,2H),3.12–3.06(m,2H),3.04–2.98(m,2H),2.83–2.75(m,2H),1.43(t,J＝7.0Hz,3H). 13 C NMR (201MHz, MeOH-d 4 ) δ170.41, 150.46, 145.88, 145.45, 135.38, 132.75, 130.57, 129.55(2C), 128.29(2C), 124.62, 112.80, 112.15, 109.11, 65 .63, 57.18, 51.56, 50.74 , 38.01 , 21.03 , 15.26. HRMS (ESI) Calcd. for C22H25N2O3 + [M+H] + : 365.1860, found: 365.1863. HPLC: 96.03% (λ=254nm, tR =12.20min).
实施例36：化合物N-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)噻吩-2-甲酰胺(I-A36)(IHCH-5211)的制备
Example 36: Compound N-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)thiophene-2-methan Preparation of Amide (I-A36) (IHCH-5211)
步骤1：将LRQ-05-137(320mg,1.48mmol)溶于DMF(10mL)后，依次加入DIPEA(1.15g,8.88mmol)和N-Boc-2-溴乙基胺(498mg,2.22mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体LRQ-06-67(293mg，收率55％)。1H NMR(800MHz,CDCl3)δ8.02(s,1H),7.15–7.09(m,1H),7.05–7.00(m,1H),6.81–6.74(m,1H),4.25(q,J＝7.0Hz,2H),3.77(s,2H),3.42–3.27(m,2H),2.99–2.92(m,2H),2.84–2.71(m,4H),1.51(t,J＝7.0Hz,3H),1.44(s,9H).HRMS(ESI)C20H29N2O4 +[M+H]+计算值：361.2122，实测值：361.2120。Step 1: After dissolving LRQ-05-137 (320mg, 1.48mmol) in DMF (10mL), add DIPEA (1.15g, 8.88mmol) and N-Boc-2-bromoethylamine (498mg, 2.22mmol) in sequence , react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1) to obtain LRQ-06-67 (293 mg, yield 55%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 )δ8.02(s,1H),7.15–7.09(m,1H),7.05–7.00(m,1H),6.81–6.74(m,1H),4.25(q,J =7.0Hz,2H),3.77(s,2H),3.42–3.27(m,2H),2.99–2.92(m,2H),2.84–2.71(m,4H),1.51(t,J=7.0Hz, 3H ), 1.44 ( s , 9H). HRMS (ESI) calcd for C20H29N2O4 + [M+H] + : 361.2122, found: 361.2120.
步骤2：将LRQ-06-67(70mg,0.19mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(150mg,1.16mmol)和2-噻吩甲酰氯(42mg,0.28mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干 燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体(14mg，收率19％)。1H NMR(800MHz,MeOH-d4)δ8.32(s,1H),7.69–7.66(m,1H),7.64–7.61(m,1H),7.13–7.08(m,2H),7.03(d,J＝7.7Hz,1H),6.82(d,J＝7.9Hz,1H),4.20(q,J＝7.0Hz,2H),3.92(s,2H),3.68–3.61(m,2H),3.10–3.04(m,2H),3.01–2.96(m,2H),2.81–2.75(m,2H),1.43(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ164.67,150.40,145.87,145.44,139.94,131.76,130.55,129.76,128.80,124.63,112.80,112.15,109.11,65.63,57.22,51.55,50.71,37.85,21.00,15.27.HRMS(ESI)C20H23N2O3S+[M+H]+计算值：371.1424，实测值：371.1430。HPLC:96.23％(λ＝254nm,tR＝12.02min)。Step 2: Dissolve LRQ-06-67 (70mg, 0.19mmol) in DCM (10mL) and cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10mL), added DIPEA (150mg, 1.16mmol) and 2-thiophenoyl chloride (42mg, 0.28mmol), and reacted at room temperature overnight. After the reaction was completed, dilute with saturated aqueous sodium bicarbonate (10 mL), extract with dichloromethane (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. After drying, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a light yellow solid (14 mg, yield 19%). 1 H NMR (800MHz, MeOH-d 4 )δ8.32(s,1H),7.69–7.66(m,1H),7.64–7.61(m,1H),7.13–7.08(m,2H),7.03(d ,J=7.7Hz,1H),6.82(d,J=7.9Hz,1H),4.20(q,J=7.0Hz,2H),3.92(s,2H),3.68–3.61(m,2H),3.10 –3.04 (m, 2H), 3.01 – 2.96 (m, 2H), 2.81 – 2.75 (m, 2H), 1.43 (t, J＝7.0Hz, 3H). 13 C NMR (201MHz, MeOH-d 4 ) δ164 .67,150.40,145.87,145.44,139.94,131.76,130.55,129.76,128.80,124.63,112.80,112.15,109.11,65.63,57.22,51.55,50.71,37.85,21. 00,15.27.HRMS(ESI)C 20 H 23 N 2 O 3 S + [M+H] + Calculated: 371.1424, Found: 371.1430. HPLC: 96.23% (λ=254nm, tR =12.02min).
实施例37：化合物2-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-3,4-双氢异喹啉-1(2H)-酮(I-A37)(IHCH-5198)的制备
Example 37: Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-3,4- Preparation of Dihydroisoquinolin-1(2H)-one(I-A37)(IHCH-5198)
步骤1，将3,4-二氢异喹啉-1(2H)-酮(526mg，3.57mmol)溶于甲苯(10mL)后降温至0℃，加入NaH(167mg，4.18mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸甲酯(639mg，4.18mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到淡黄色油状液体LRQ-06-23(746mg，收率95％)。1H NMR(800MHz,CDCl3)δ8.01–7.96(m,1H),7.37–7.31(m,1H),7.25(t,J＝7.6Hz,1H),7.10(d,J＝7.6Hz,1H),4.26(s,2H),3.66(s,3H),3.57(t,J＝6.7Hz,2H),2.99–2.93(m,2H).HRMS(ESI)C12H14NO3 +[M+H]+计算值：220.0968，实测值：220.0972。Step 1: Dissolve 3,4-dihydroisoquinolin-1(2H)-one (526mg, 3.57mmol) in toluene (10mL) and cool down to 0°C, add NaH (167mg, 4.18mmol), reflux reaction 1 Hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (639 mg, 4.18 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate /petroleum ether=1:4) to obtain light yellow oily liquid LRQ-06-23 (746 mg, yield 95%). 1 H NMR (800MHz, CDCl 3 ) δ8.01–7.96(m,1H),7.37–7.31(m,1H),7.25(t,J=7.6Hz,1H),7.10(d,J=7.6Hz, 1H), 4.26(s, 2H), 3.66(s, 3H), 3.57(t, J=6.7Hz, 2H), 2.99–2.93(m, 2H). HRMS(ESI) C 12 H 14 NO 3 + [ M+H]+ calculated: 220.0968, found: 220.0972.
步骤2，将LRQ-06-23(526mg，2.40mmol)溶于THF(10mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(7mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-06-24，无需纯化直接投入下一步反应。HRMS(ESI)C11H14NO2 +[M+H]+计算值：192.1019，实测值：192.1015。Step 2, LRQ-06-23 (526mg, 2.40mmol) was dissolved in THF (10mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (7mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-24, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H14NO2 + [M+H]+: 192.1019 , found : 192.1015.
步骤3，将LRQ-06-24溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.19g,3.60mmol)和三苯基膦(1.26g,4.80mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-06-22(255mg，两步反应收率42％)。1H NMR(800MHz,CDCl3) δ8.09–8.05(m,1H),7.46–7.41(m,1H),7.38–7.33(m,1H),7.19(d,J＝7.5Hz,1H),3.95(t,J＝6.3Hz,2H),3.72(t,J＝6.5Hz,2H),3.65(t,J＝6.3Hz,2H),3.07–3.03(m,2H).HRMS(ESI)C11H13BrNO+[M+H]+计算值：254.0175，实测值：254.0179。Step 3: Dissolve LRQ-06-24 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.19g, 3.60mmol) and triphenylphosphine (1.26g, 4.80mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4) to obtain LRQ-06-22 (255 mg, two-step reaction yield 42%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ8.09–8.05(m,1H),7.46–7.41(m,1H),7.38–7.33(m,1H),7.19(d,J=7.5Hz,1H),3.95(t,J=6.3Hz, 2H), 3.72(t, J=6.5Hz, 2H), 3.65(t, J=6.3Hz, 2H), 3.07–3.03(m, 2H).HRMS(ESI)C 11 H 13 BrNO + [M+H ] + calculated value: 254.0175, measured value: 254.0179.
步骤4，将LRQ-05-137(40mg，0.19mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-22(74mg，0.29mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(15mg，收率21％)。1H NMR(800MHz,MeOH-d4)δ7.94–7.90(m,1H),7.46–7.40(m,1H),7.35–7.29(m,1H),7.23(d,J＝7.4Hz,1H),7.11–7.06(m,1H),7.03–6.99(m,1H),6.81–6.77(m,1H),4.21(q,J＝7.0Hz,2H),3.87–3.78(m,4H),3.70–3.61(m,2H),3.04–2.99(m,2H),2.99–2.96(m,2H),2.96–2.90(m,2H),2.77–2.69(m,2H),1.44(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ166.61,151.61,145.73,145.26,140.05,133.10,130.79,130.12,128.61,128.21,127.91,124.36,112.75,112.05,108.87,65.59,55.49,51.46,51.06,47.81,46.02,28.81,21.49,15.28.HRMS(ESI)C24H27N2O3 +[M+H]+计算值：391.2016，实测值：391.2011。HPLC:98.96％(λ＝254nm,tR＝11.33min)。Step 4, after dissolving LRQ-05-137 (40mg, 0.19mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-06-22 (74mg, 0.29mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (15 mg, yield 21%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.94–7.90(m,1H),7.46–7.40(m,1H),7.35–7.29(m,1H),7.23(d,J=7.4Hz,1H ),7.11–7.06(m,1H),7.03–6.99(m,1H),6.81–6.77(m,1H),4.21(q,J＝7.0Hz,2H),3.87–3.78(m,4H), 3.70–3.61(m,2H),3.04–2.99(m,2H),2.99–2.96(m,2H),2.96–2.90(m,2H),2.77–2.69(m,2H),1.44(t,J ＝7.0Hz, 3H). 13 C NMR (201MHz, MeOH-d 4 ) δ166.61, 151.61, 145.73, 145.26, 140.05, 133.10, 130.79, 130.12, 128.61, 128.21, 127.91, 124.36, 112.75 ,112.05,108.87,65.59, 55.49, 51.46, 51.06, 47.81, 46.02, 28.81, 21.49, 15.28. HRMS (ESI) Calculated for C 24 H 27 N 2 O 3 + [M+H]+: 391.2016, Found: 391.2011. HPLC: 98.96% (λ=254nm, tR =11.33min).
实施例38：化合物2-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-6-甲基-3,4-三氢-2,7-萘吡啶-1(2H)-酮(I-A38)(IHCH-5199)的制备
Example 38: Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-6-methyl Preparation of -3,4-trihydro-2,7-naphthyridin-1(2H)-one (I-A38)(IHCH-5199)
步骤1，将4-氯-6-甲基烟碱酸甲酯(4.03g,21.78mmol)，三丁基乙烯基锡(10.36g,32.67mmol)和四(三苯基膦)钯(1.76g,1.52mmol)溶于甲苯(10mL)和1,4-二氧六环(10mL)，氮气置换三次后，将反应液升温至90℃反应过夜。反应完毕后，加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到橙黄色油状液体LRQ-06-05(3.2g，收率83％)。1H NMR(800MHz,CDCl3)δ8.99(s,1H),7.55–7.47(m,1H),7.32(s,1H),5.84(d,J＝17.5Hz,1H),5.53(d,J＝11.0Hz,1H),3.92(s,3H),2.61(s,3H).HRMS(ESI)C10H12NO2 +[M+H]+计算值：178.0863，实测值：178.0868。Step 1, methyl 4-chloro-6-methylnicotinate (4.03g, 21.78mmol), tributylvinyltin (10.36g, 32.67mmol) and tetrakis(triphenylphosphine) palladium (1.76g , 1.52 mmol) was dissolved in toluene (10 mL) and 1,4-dioxane (10 mL), and after nitrogen replacement three times, the temperature of the reaction solution was raised to 90° C. to react overnight. After the reaction was completed, dilute with saturated aqueous sodium bicarbonate solution (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography. Purification (ethyl acetate/petroleum ether=1:10) gave orange-yellow oily liquid LRQ-06-05 (3.2 g, yield 83%). 1 H NMR (800MHz, CDCl 3 ) δ8.99(s, 1H), 7.55–7.47(m, 1H), 7.32(s, 1H), 5.84(d, J=17.5Hz, 1H), 5.53(d, J = 11.0 Hz, 1H), 3.92(s, 3H), 2.61(s, 3H). HRMS (ESI) Calcd. for C 10 H 12 NO 2 + [M+H]+: 178.0863, Found: 178.0868.
步骤2，在封管中将LRQ-06-05(3.20g,18.08mmol)与50ml氨(50mL,7.0M甲醇溶液)混合后，将反应液升温至100℃搅拌过夜。反应完毕后，减压蒸除溶剂得到粉色固体LRQ-06-06，无需纯化直接投入下一步反应。HRMS(ESI)C9H11N2O+[M+H]+计算值：163.0866，实测值：163.0869。 Step 2, after mixing LRQ-06-05 (3.20g, 18.08mmol) and 50ml ammonia (50mL, 7.0M methanol solution) in a sealed tube, the reaction solution was heated to 100°C and stirred overnight. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a pink solid LRQ-06-06, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C9H11N2O + [M+H]+: 163.0866 , found: 163.0869 .
步骤3，将LRQ-06-06溶于甲苯(10mL)后降温至0℃，加入NaH(844mg，21.17mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸甲酯(3.23g，21.17mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-06-25(3.72g，两步反应收率88％)。1H NMR(800MHz,CDCl3)δ9.09(s,1H),7.02(s,1H),4.34(s,2H),3.76(s,3H),3.67(t,J＝6.6Hz,2H),3.03(t,J＝6.6Hz,2H),2.60(s,3H).HRMS(ESI)C12H15N2O3 +[M+H]+计算值：235.1077，实测值：235.1082。Step 3: Dissolve LRQ-06-06 in toluene (10 mL) and cool down to 0°C, add NaH (844 mg, 21.17 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (3.23 g, 21.17 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate /petroleum ether=1:4) to obtain a yellow solid LRQ-06-25 (3.72 g, two-step reaction yield 88%). 1 H NMR (800MHz, CDCl 3 ) δ9.09(s,1H),7.02(s,1H),4.34(s,2H),3.76(s,3H),3.67(t,J=6.6Hz,2H) , 3.03 (t, J = 6.6 Hz, 2H), 2.60 (s, 3H). HRMS (ESI) Calculated for C 12 H 15 N 2 O 3 + [M+H]+: 235.1077, Found: 235.1082.
步骤4，将LRQ-06-25(600mg，2.56mmol)溶于THF(10mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(8mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-06-26，无需纯化直接投入下一步反应。HRMS(ESI)C11H15N2O2 +[M+H]+计算值：207.1128，实测值：207.1130。Step 4, LRQ-06-25 (600mg, 2.56mmol) was dissolved in THF (10mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-26, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H15N2O2 + [M+H]+: 207.1128 , found : 207.1130.
步骤5，将LRQ-06-26溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.27g,3.84mmol)和三苯基膦(1.34g,5.12mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到黄色固体LRQ-06-27(206mg，两步反应收率30％)。1H NMR(800MHz,MeOH-d4)δ8.95(s,1H),7.76(s,1H),3.83(t,J＝6.6Hz,2H),3.80(t,J＝5.5Hz,2H),3.73–3.69(m,2H),3.28(t,J＝6.6Hz,2H),2.76(s,3H).HRMS(ESI)C11H14BrN2O+[M+H]+计算值：269.0284，实测值：269.0283。Step 5: Dissolve LRQ-06-26 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.27g, 3.84mmol) and triphenylphosphine (1.34g, 5.12mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4) to obtain LRQ-06-27 (206 mg, two-step reaction yield 30%) as a yellow solid. 1 H NMR (800MHz, MeOH-d 4 )δ8.95(s,1H),7.76(s,1H),3.83(t,J=6.6Hz,2H),3.80(t,J=5.5Hz,2H) ,3.73–3.69(m,2H),3.28(t,J＝6.6Hz,2H),2.76(s,3H).HRMS(ESI)C 11 H 14 BrN 2 O + [M+H]+ calculated value: 269.0284, found: 269.0283.
步骤6，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg，1.48mmol)，LRQ-06-27(94mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(27mg，收率29％)。1H NMR(800MHz,CDCl3)δ9.07(s,1H),7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.96(s,1H),6.77(d,J＝7.9Hz,1H),4.27–4.21(m,2H),3.88–3.76(m,4H),3.69–3.62(m,2H),3.03–2.96(m,2H),2.95–2.90(m,4H),2.77–2.70(m,2H),2.56(s,3H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ163.36,161.52,150.69,149.22,147.00,144.54,143.86,129.70,123.34,122.65,121.06,111.89,111.14,107.24,64.51,54.78,50.55,50.30,46.56,45.26,27.66,24.62,20.81,15.01.HRMS(ESI)C24H28N3O3 +[M+H]+计算值：406.2125，实测值：406.2121。HPLC:95.82％(λ＝254nm,tR＝11.88min)。Step 6, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (191mg, 1.48mmol) and LRQ-06-27 (94mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (27 mg, yield 29%). 1 H NMR (800MHz, CDCl 3 ) δ9.07(s, 1H), 7.11(t, J=7.8Hz, 1H), 7.02(d, J=7.7Hz, 1H), 6.96(s, 1H), 6.77 (d,J=7.9Hz,1H),4.27–4.21(m,2H),3.88–3.76(m,4H),3.69–3.62(m,2H),3.03–2.96(m,2H),2.95–2.90 (m,4H),2.77–2.70(m,2H),2.56(s,3H),1.50(t,J＝7.0Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ163.36,161.52,150.69,149.22 ,147.00,144.54,143.86,129.70,123.34,122.65,121.06,111.89,111.14,107.24,64.51,54.78,50.55,50.30,46.56,45.26,27.66,24.62,20 .81,15.01.HRMS(ESI)C 24 H 28 N 3 O 3 + [M+H]+ Calculated: 406.2125, Found: 406.2121. HPLC: 95.82% (λ=254nm, tR =11.88min).
实施例39：化合物5-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-2,3-二甲基-2,5,6,7-四氢-4H-吡唑并[4,3-c]吡啶-4-酮(I-A39)(IHCH-5216)的制备
Example 39: Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-2,3- Preparation of Dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (I-A39)(IHCH-5216)
步骤1，将3-溴-1,5-二甲基-1H-吡唑-4-羧酸甲酯(0.46g,2.04mmol)，2((叔丁氧羰基)氨基)乙基三氟硼酸钾(0.76g,3.04mmol)，碳酸铯(1.64g,5.06mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(0.16g,0.18mmol)溶于甲苯(16mL)和水(8mL)，氮气置换三次后，将反应液升温至100℃反应3小时。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到橙黄色油状液体LRQ-06-71，无需纯化直接投入下一步反应。HRMS(ESI)C14H24N3O4 +[M+H]+计算值：298.1761，实测值：298.1760。Step 1, methyl 3-bromo-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.46g, 2.04mmol), 2((tert-butoxycarbonyl)amino)ethyltrifluoroboronic acid Potassium (0.76g, 3.04mmol), cesium carbonate (1.64g, 5.06mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex ( 0.16g, 0.18mmol) was dissolved in toluene (16mL) and water (8mL), and after nitrogen replacement three times, the temperature of the reaction solution was raised to 100°C for 3 hours. After the reaction, add water (10mL) to dilute, extract with ethyl acetate (20mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain orange-yellow oily liquid LRQ-06-71, directly without purification into the next reaction. HRMS (ESI) calcd for C14H24N3O4 + [M+H]+: 298.1761 , found : 298.1760.
步骤2，将LRQ-06-71溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后，减压蒸除溶剂得到淡黄色油状液体LRQ-06-71-NH2，无需纯化直接投入下一步反应。HRMS(ESI)C9H16N3O2 +[M+H]+计算值：198.1237，实测值：198.1239。Step 2: Dissolve LRQ-06-71 in DCM (10 mL) and cool down to 0° C., add trifluoroacetic acid (1 mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a light yellow oily liquid LRQ-06-71-NH2, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C9H16N3O2 + [M+H]+: 198.1237 , found : 198.1239.
步骤3，将LRQ-06-71-NH2溶于甲醇(10mL)后，加入甲醇钠(2mL,5.0M甲醇溶液)室温反应0.5小时。反应完毕减压蒸除溶剂后，加水(10mL)稀释，二氯甲烷(20mL*3)萃取，水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色固体LRQ-06-72，无需纯化直接投入下一步反应。HRMS(ESI)C8H12N3O+[M+H]+计算值：166.0975，实测值：166.0969。Step 3, after dissolving LRQ-06-71-NH2 in methanol (10mL), add sodium methoxide (2mL, 5.0M methanol solution) to react at room temperature for 0.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, diluted with water (10mL), extracted with dichloromethane (20mL*3), washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain LRQ-06-72 as a light yellow solid. Purified directly into the next reaction. HRMS ( ESI ) calcd. for C8H12N3O + [M+H]+: 166.0975 , found: 166.0969.
步骤4，将LRQ-06-72溶于甲苯(10mL)后降温至0℃，加入NaH(94mg，2.36mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸乙酯(394mg，2.36mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体LRQ-06-75(220mg，四步反应收率43％)。1H NMR(800MHz,CDCl3)δ4.24(s,2H),4.20(q,J＝7.1Hz,2H),3.79–3.73(m,3H),3.67–3.62(m,2H),3.00–2.91(m,2H),2.56–2.50(m,3H),1.28(t,J＝7.1Hz,3H).HRMS(ESI)C12H18N3O3 +[M+H]+计算值：252.1343，实测值：252.1341。Step 4: Dissolve LRQ-06-72 in toluene (10 mL) and cool down to 0°C, add NaH (94 mg, 2.36 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, ethyl bromoacetate (394 mg, 2.36 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate /petroleum ether=1:1) to obtain light yellow solid LRQ-06-75 (220mg, four-step reaction yield 43%). 1 H NMR (800MHz, CDCl 3 )δ4.24(s,2H),4.20(q,J=7.1Hz,2H),3.79–3.73(m,3H),3.67–3.62(m,2H),3.00– 2.91(m,2H),2.56–2.50(m,3H),1.28(t,J＝7.1Hz,3H).HRMS(ESI)C 12 H 18 N 3 O 3 + [M+H]+calculated value: 252.1343, Found: 252.1341.
步骤5，将LRQ-06-75(220mg，0.87mmol)溶于THF(5mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(3mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应 完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-06-77，无需纯化直接投入下一步反应。HRMS(ESI)C10H16N3O2 +[M+H]+计算值：210.1237，实测值：210.1238。Step 5, LRQ-06-75 (220mg, 0.87mmol) was dissolved in THF (5mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (3mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. reaction After completion, add saturated potassium sodium tartrate aqueous solution (10mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain light yellow oily liquid LRQ -06-77, directly put into the next reaction without purification. HRMS (ESI) calcd for C10H16N3O2 + [M+H]+: 210.1237 , found : 210.1238.
步骤6，将LRQ-06-77溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(432mg,1.31mmol)和三苯基膦(456mg,1.74mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体LRQ-06-78(40mg，两步反应收率17％)。1H NMR(600MHz,CDCl3)δ3.87(t,J＝6.4Hz,2H),3.83(s,3H),3.72(t,J＝6.6Hz,2H),3.57(t,J＝6.4Hz,2H),2.99(t,J＝6.5Hz,2H),2.55(s,3H).HRMS(ESI)C10H15BrN3O+[M+H]+计算值：272.0393，实测值：272.0391。Step 6: Dissolve LRQ-06-77 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (432mg, 1.31mmol) and triphenylphosphine (456mg, 1.74mmol) in sequence, and react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1) to obtain LRQ-06-78 (40 mg, two-step reaction yield 17%) as a yellow solid. 1 H NMR (600MHz, CDCl 3 ) δ3.87(t, J=6.4Hz, 2H), 3.83(s, 3H), 3.72(t, J=6.6Hz, 2H), 3.57(t, J=6.4Hz ,2H),2.99(t,J＝6.5Hz,2H),2.55(s,3H).HRMS(ESI)C 10 H 15 BrN 3 O + [M+H]+calculated: 272.0393, found: 272.0391 .
步骤7，将LRQ-05-137(22mg，0.10mmol)溶于DMF(8mL)后，依次加入DIPEA(78mg，0.60mmol)，LRQ-06-78(40mg，0.15mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(6mg，收率14％)。1H NMR(800MHz,CDCl3)δ7.11(t,J＝7.8Hz,1H),7.02(d,J＝7.7Hz,1H),6.78–6.73(m,1H),4.25(q,J＝7.0Hz,2H),3.79(s,2H),3.74(s,3H),3.72–3.69(m,2H),3.65–3.62(m,2H),2.97–2.91(m,2H),2.88–2.83(m,4H),2.73–2.71(m,2H),2.53(s,3H),1.50(t,J＝7.0Hz,3H).HRMS(ESI)C23H29N4O3 +[M+H]+计算值：409.2234，实测值：409.2237。HPLC:95.42％(λ＝254nm,tR＝12.10min)。Step 7, after dissolving LRQ-05-137 (22mg, 0.10mmol) in DMF (8mL), add DIPEA (78mg, 0.60mmol) and LRQ-06-78 (40mg, 0.15mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (6 mg, yield 14%). 1 H NMR (800MHz, CDCl 3 ) δ7.11(t, J=7.8Hz, 1H), 7.02(d, J=7.7Hz, 1H), 6.78–6.73(m, 1H), 4.25(q, J= 7.0Hz, 2H), 3.79(s, 2H), 3.74(s, 3H), 3.72–3.69(m, 2H), 3.65–3.62(m, 2H), 2.97–2.91(m, 2H), 2.88–2.83 (m,4H),2.73–2.71(m,2H),2.53(s,3H),1.50(t,J＝7.0Hz,3H).HRMS(ESI)C 23 H 29 N 4 O 3 + [M+ H]+ calculated value: 409.2234, measured value: 409.2237. HPLC: 95.42% (λ=254nm, tR =12.10min).
实施例40：化合物2-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-1-酮(I-A40)(IHCH-5209)的制备
Example 40: Compound 2-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-2,3, 4,5-Tetrahydro-1H-benzo[c]azepine Preparation of -1-ketone (I-A40) (IHCH-5209)
步骤1，将2,3,4,5-四氢-1H-2-苯并氮杂-1-酮(1.00g，6.20mmol)溶于甲苯(10mL)后降温至0℃，加入NaH(290mg，7.26mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸甲酯(1.11g，7.26mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:2)，得到淡黄色油状液体LRQ-06-49(1.20g，收率83％)。1H NMR(800MHz,CDCl3)δ7.71–7.67(m,1H),7.41–7.37(m,1H),7.35–7.30(m,1H),7.18–7.14(m,1H),4.36(s,2H),3.77(s,3H),3.33 –3.25(m,2H),2.94–2.84(m,2H),2.16–2.00(m,2H).HRMS(ESI)C13H16NO3 +[M+H]+计算值：234.1125，实测值：234.1127。Step 1, the 2,3,4,5-tetrahydro-1H-2-benzazepine -1-Kone (1.00g, 6.20mmol) was dissolved in toluene (10mL) and cooled to 0°C, NaH (290mg, 7.26mmol) was added and refluxed for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.11 g, 7.26 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate /petroleum ether=1:2) to obtain light yellow oily liquid LRQ-06-49 (1.20 g, yield 83%). 1 H NMR (800MHz, CDCl 3 ) δ7.71–7.67(m,1H),7.41–7.37(m,1H),7.35–7.30(m,1H),7.18–7.14(m,1H),4.36(s ,2H),3.77(s,3H),3.33 –3.25(m,2H),2.94–2.84(m,2H),2.16–2.00(m,2H).HRMS(ESI)C 13 H 16 NO 3 + [M+H]+Calculated value: 234.1125, measured value : 234.1127.
步骤2，将LRQ-06-49(1.00g，4.30mmol)溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(13mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色固体LRQ-06-52，无需纯化直接投入下一步反应。HRMS(ESI)C12H16NO2 +[M+H]+计算值：206.1176，实测值：206.1180。Step 2, LRQ-06-49 (1.00g, 4.30mmol) was dissolved in THF (20mL). After nitrogen replacement three times, the reaction solution was cooled to -10°C, and DIBAL-H (13mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-52, directly put into the next reaction without purification. HRMS (ESI) calcd for C12H16NO2 + [M+H]+: 206.1176, found : 206.1180 .
步骤3，将LRQ-06-52溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(2.14g,6.45mmol)和三苯基膦(2.26g,8.60mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯)，得到淡黄色油状液体LRQ-06-54(69mg，两步反应收率6％)。1H NMR(600MHz,CDCl3)δ7.70–7.64(m,1H),7.41–7.36(m,1H),7.36–7.30(m,1H),7.15(d,J＝7.3Hz,1H),4.01–3.92(m,2H),3.69–3.60(m,2H),3.37–3.26(m,2H),2.88–2.79(m,2H),2.15–2.02(m,2H).HRMS(ESI)C12H15BrNO+[M+H]+计算值：268.0332，实测值：268.0334。Step 3: Dissolve LRQ-06-52 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (2.14g, 6.45mmol) and triphenylphosphine (2.26g, 8.60mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate) , to obtain light yellow oily liquid LRQ-06-54 (69mg, two-step reaction yield 6%). 1 H NMR (600MHz, CDCl 3 ) δ7.70–7.64(m,1H),7.41–7.36(m,1H),7.36–7.30(m,1H),7.15(d,J=7.3Hz,1H), 4.01–3.92(m,2H),3.69–3.60(m,2H),3.37–3.26(m,2H),2.88–2.79(m,2H),2.15–2.02(m,2H).HRMS(ESI)C 12 H 15 BrNO + [M+H]+ calcd: 268.0332, found: 268.0334.
步骤4，将LRQ-05-137(40mg，0.19mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-54(69mg，0.28mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(17mg，收率23％)。1H NMR(800MHz,CDCl3)δ7.65(d,J＝7.5Hz,1H),7.34(t,J＝7.4Hz,1H),7.30(t,J＝7.5Hz,1H),7.14–7.08(m,2H),7.02(d,J＝7.7Hz,1H),6.76(d,J＝7.9Hz,1H),4.24(q,J＝7.0Hz,2H),3.84–3.80(m,2H),3.79(s,2H),3.24(t,J＝6.4Hz,2H),2.97–2.92(m,2H),2.92–2.87(m,2H),2.79–2.75(m,2H),2.75–2.69(m,2H),2.05–1.98(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ171.29,151.23,144.56,143.86,137.68,136.37,130.82,129.87,128.57,128.27,126.96,123.27,111.95,111.16,107.12,64.51,55.78,50.66,50.36,47.37,45.72,30.38,30.32,21.03,15.05.HRMS(ESI)C25H29N2O3 +[M+H]+计算值：405.2173，实测值：405.2180。HPLC:96.07％(λ＝254nm,tR＝12.48min)。Step 4, after dissolving LRQ-05-137 (40mg, 0.19mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-06-54 (69mg, 0.28mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (17 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 ) δ7.65(d, J=7.5Hz, 1H), 7.34(t, J=7.4Hz, 1H), 7.30(t, J=7.5Hz, 1H), 7.14–7.08 (m,2H),7.02(d,J=7.7Hz,1H),6.76(d,J=7.9Hz,1H),4.24(q,J=7.0Hz,2H),3.84–3.80(m,2H) ,3.79(s,2H),3.24(t,J＝6.4Hz,2H),2.97–2.92(m,2H),2.92–2.87(m,2H),2.79–2.75(m,2H),2.75–2.69 (m,2H),2.05–1.98(m,2H),1.50(t,J=7.0Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ171.29,151.23,144.56,143.86,137.68,136.37,130.82, 129.87, 128.57, 128.27, 126.96, 123.27, 111.95, 111.16, 107.12, 64.51, 55.78, 50.66, 50.36, 47.37, 45.72, 30.38, 30.32, 21.03, 15.05. HRMS (ESI )C 25 H 29 N 2 O 3 + [ M+H]+ calculated value: 405.2173, found value: 405.2180. HPLC: 96.07% (λ=254nm, tR =12.48min).
实施例41：化合物5-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-1-甲基-5,6,7,8-四氢吡咯[3,2-c]氮杂-4(1H)-1-酮(I-A41)(IHCH-5210)的制备
Example 41: Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1-methyl -5,6,7,8-Tetrahydropyrrole[3,2-c]azepine - Preparation of 4(1H)-1-one (I-A41) (IHCH-5210)
步骤1，将氮杂环庚烷-2,4-二酮(1.00g，7.86mmol)溶于N-甲基吡咯烷酮(20mL)后，依次加入甲氨基乙醛缩二甲醇(9.37g，78.65mmol)，甲磺酸(1mL)和无水硫酸镁(5.68g，47.16mmol)，然后反应液升温至110℃反应1小时。随后将反应液升温至150℃反应2小时。反应完毕后，将反应液降温至室温，加10％氢氧化钠水溶液调节pH至9，二氯甲烷(20mL*3)萃取，水洗，无水硫酸钠干燥后，减压蒸除溶剂得到红色油状液体LRQ-06-56，无需纯化直接投入下一步反应。HRMS(ESI)C9H13N2O+[M+H]+计算值：165.1022，实测值：165.1026。Step 1, after dissolving azepane-2,4-dione (1.00g, 7.86mmol) in N-methylpyrrolidone (20mL), add methylaminoacetaldehyde dimethyl acetal (9.37g, 78.65mmol ), methanesulfonic acid (1 mL) and anhydrous magnesium sulfate (5.68 g, 47.16 mmol), and then the reaction solution was heated to 110 ° C for 1 hour. Subsequently, the temperature of the reaction solution was raised to 150° C. for 2 hours. After the reaction is complete, cool the reaction solution to room temperature, add 10% aqueous sodium hydroxide solution to adjust the pH to 9, extract with dichloromethane (20mL*3), wash with water, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a red oil Liquid LRQ-06-56, directly put into the next reaction without purification. HRMS (ESI) calcd for C9H13N2O + [M+H]+: 165.1022 , found : 165.1026.
步骤2，将LRQ-06-56溶于甲苯(10mL)后降温至0℃，加入NaH(368mg，9.20mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸甲酯(1.41g，9.20mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体LRQ-06-57(909mg，两步反应收率49％)。1H NMR(800MHz,CDCl3)δ6.70(d,J＝3.0Hz,1H),6.57–6.54(m,1H),4.33(s,2H),3.73(s,3H),3.54–3.48(m,5H),2.83–2.78(m,2H),2.27–2.18(m,2H).HRMS(ESI)C12H17N2O3 +[M+H]+计算值：237.1234，实测值：237.1237。Step 2: Dissolve LRQ-06-56 in toluene (10 mL) and cool down to 0°C, add NaH (368 mg, 9.20 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.41 g, 9.20 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10 mL), extract with ethyl acetate (20 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate /petroleum ether=1:1) to obtain LRQ-06-57 (909 mg, two-step reaction yield 49%) as a pale yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ6.70 (d, J=3.0Hz, 1H), 6.57–6.54 (m, 1H), 4.33 (s, 2H), 3.73 (s, 3H), 3.54–3.48 ( m,5H),2.83–2.78(m,2H),2.27–2.18(m,2H).HRMS(ESI)C 12 H 17 N 2 O 3 + [M+H]+ calculated value: 237.1234, measured value: 237.1237.
步骤3，将LRQ-06-57(400mg，1.69mmol)溶于THF(20mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(5mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色油状液体LRQ-06-58，无需纯化直接投入下一步反应。HRMS(ESI)C11H17N2O2 +[M+H]+计算值：209.1285，实测值：209.1287。Step 3, LRQ-06-57 (400mg, 1.69mmol) was dissolved in THF (20mL), the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (5mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-58, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H17N2O2 + [M+H]+: 209.1285 , found : 209.1287.
步骤4，将LRQ-06-58溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(841mg,2.54mmol)和三苯基膦(887mg,3.38mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯)，得到黑色固体LRQ-06-59(200mg，两步反应收率44％)。1H NMR(800MHz,MeOH-d4)δ6.88–6.85(m,1H),6.59(d,J＝3.2Hz,1H),4.94–4.89(m,2H),4.26–4.21(m,2H),3.87–3.83(m,2H),3.66(s,3H),3.13–3.05(m,2H),2.33–2.24(m,2H).HRMS(ESI)C11H16BrN2O+[M+H]+计算值：271.0441，实测值：271.0441。Step 4: Dissolve LRQ-06-58 in DCM (10 mL) and cool down to 0°C, add carbon tetrabromide (841 mg, 2.54 mmol) and triphenylphosphine (887 mg, 3.38 mmol) in sequence, and react overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate) , to obtain black solid LRQ-06-59 (200mg, two-step reaction yield 44%). 1 H NMR (800MHz, MeOH-d 4 ) δ6.88–6.85 (m, 1H), 6.59 (d, J=3.2Hz, 1H), 4.94–4.89 (m, 2H), 4.26–4.21 (m, 2H ),3.87–3.83(m,2H),3.66(s,3H),3.13–3.05(m,2H),2.33–2.24(m,2H).HRMS(ESI)C 11 H 16 BrN 2 O + [M +H]+ calculated value: 271.0441, measured value: 271.0441.
步骤5，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg， 1.48mmol)，LRQ-06-59(95mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(48mg，收率51％)。1H NMR(800MHz,CDCl3)δ7.10(t,J＝7.8Hz,1H),7.01(d,J＝7.6Hz,1H),6.75(d,J＝7.9Hz,1H),6.67(d,J＝2.9Hz,1H),6.56–6.52(m,1H),4.24(q,J＝7.0Hz,2H),3.80–3.73(m,4H),3.50–3.43(m,5H),2.97–2.90(m,2H),2.86–2.81(m,2H),2.77–2.73(m,2H),2.73–2.66(m,2H),2.14–2.07(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ166.22,151.34,144.54,143.86,133.06,129.93,123.24,121.57,117.23,111.95,111.17,110.79,107.14,64.54,55.46,50.69,50.32,49.26,47.45,34.16,26.60,26.45,21.01,15.06.HRMS(ESI)C24H30N3O3 +[M+H]+计算值：408.2282，实测值：408.2279。HPLC:96.12％(λ＝254nm,tR＝12.07min)。Step 5, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (191mg, 1.48mmol), LRQ-06-59 (95mg, 0.35mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a light yellow solid (48 mg, yield 51%). 1 H NMR (800MHz, CDCl 3 ) δ7.10(t, J=7.8Hz, 1H), 7.01(d, J=7.6Hz, 1H), 6.75(d, J=7.9Hz, 1H), 6.67(d ,J=2.9Hz,1H),6.56–6.52(m,1H),4.24(q,J=7.0Hz,2H),3.80–3.73(m,4H),3.50–3.43(m,5H),2.97– 2.90(m,2H),2.86–2.81(m,2H),2.77–2.73(m,2H),2.73–2.66(m,2H),2.14–2.07(m,2H),1.50(t,J＝7.0 Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ166.22,151.34,144.54,143.86,133.06,129.93,123.24,121.57,117.23,111.95,111.17,110.79,107.14,64.54 ,55.46,50.69,50.32,49.26, 47.45, 34.16, 26.60, 26.45, 21.01, 15.06. HRMS (ESI) Calculated for C 24 H 30 N 3 O 3 + [M+H]+: 408.2282, Found: 408.2279. HPLC: 96.12% (λ=254nm, tR =12.07min).
实施例42：化合物5-(2-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-1-甲基-5,6,7,8-四氢吡唑并[4,3-c]氮杂-4(1H)-酮(I-A42)(IHCH-5207)的制备
Example 42: Compound 5-(2-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1-methyl -5,6,7,8-Tetrahydropyrazolo[4,3-c]azepine Preparation of -4(1H)-ketone (I-A42) (IHCH-5207)
步骤1，将1-甲基-1,5,6,7-四氢-4H-吲唑-4-酮(1.00g,6.66mmol)，乙酸钠(1.05g,4.20mmol)，和盐酸羟胺(0.21g,0.25mmol)溶于无水乙醇(16mL)后，将反应液升温至60℃反应过夜。反应完毕后过滤反应混合物，滤液减压蒸除溶剂，得到白色固体LRQ-06-47-1，无需纯化直接投入下一步反应。HRMS(ESI)C8H12N3O+[M+H]+计算值：166.0975，实测值：166.0977。Step 1, 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one (1.00g, 6.66mmol), sodium acetate (1.05g, 4.20mmol), and hydroxylamine hydrochloride ( 0.21g, 0.25mmol) was dissolved in absolute ethanol (16mL), and the reaction solution was heated to 60°C for overnight reaction. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain a white solid LRQ-06-47-1, which was directly put into the next reaction without purification. HRMS ( ESI ) calcd for C8H12N3O + [M+H]+: 166.0975, found : 166.0977.
步骤2，将LRQ-06-47-1和三乙胺(2.02g,19.98mmol)，溶于DCM(20mL)，加入对甲苯磺酰氯(1.46g,7.66mmol)后，回流反应0.5小时。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到黄色固体后将其溶于三氟乙酸(5mL)，回流反应0.5小时。反应完毕后减压蒸除溶剂，加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(50mL*3)萃取，水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到黄色固体LRQ-04-47，无需纯化直接投入下一步反应。HRMS(ESI)C8H12N3O+[M+H]+计算值：166.0975，实测值：166.0975.Step 2, LRQ-06-47-1 and triethylamine (2.02g, 19.98mmol) were dissolved in DCM (20mL), after p-toluenesulfonyl chloride (1.46g, 7.66mmol) was added, the reaction was refluxed for 0.5 hours. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain a yellow solid, which was dissolved in three Fluoroacetic acid (5 mL) was refluxed for 0.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (50 mL*3), washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a yellow solid LRQ- 04-47, directly put into the next reaction without purification. HRMS(ESI) Calculated for C 8 H 12 N 3 O + [M+H]+: 166.0975, Found: 166.0975.
步骤3，将LRQ-04-47溶于甲苯(10mL)后降温至0℃，加入NaH(311mg，7.79mmol)，回流反应1小时。然后反应液降温至室温，加入溴代乙酸甲酯(1.19g，7.79mmol)，回流反应过夜。反应完毕后，加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减 压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到淡黄色固体LRQ-06-50(620mg，三步反应收率39％)。1H NMR(800MHz,CDCl3)δ8.16(s,1H),4.71(s,2H),3.80(s,3H),3.77(s,3H),2.71(t,J＝6.2Hz,2H),2.55–2.45(m,2H),2.08–1.98(m,2H)HRMS(ESI)C11H16N3O3 +[M+H]+计算值：238.1186，实测值：238.1187。Step 3: Dissolve LRQ-04-47 in toluene (10 mL) and cool down to 0°C, add NaH (311 mg, 7.79 mmol), and reflux for 1 hour. Then the reaction solution was cooled to room temperature, methyl bromoacetate (1.19 g, 7.79 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, dilute with water (10mL), extract with ethyl acetate (20mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and reduce The solvent was removed by pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain LRQ-06-50 (620 mg, three-step reaction yield 39%) as a light yellow solid. 1 H NMR (800MHz, CDCl 3 )δ8.16(s,1H),4.71(s,2H),3.80(s,3H),3.77(s,3H),2.71(t,J＝6.2Hz,2H) , 2.55–2.45 (m,2H), 2.08–1.98 (m,2H) HRMS (ESI) Calculated for C 11 H 16 N 3 O 3 + [M+H]+: 238.1186, Found: 238.1187.
步骤4，将LRQ-06-50(600mg，2.53mmol)溶于THF(5mL)，氮气置换三次后将反应液降温至-10℃，加入DIBAL-H(8mL,1.0M四氢呋喃溶液)。然后将反应液升温至0℃反应6小时。反应完毕后加饱和酒石酸钾钠水溶液(10mL)，随后室温搅拌1小时，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到淡黄色固体LRQ-06-53，无需纯化直接投入下一步反应。HRMS(ESI)C10H16N3O2 +[M+H]+计算值：210.1237，实测值：210.1242。Step 4, LRQ-06-50 (600mg, 2.53mmol) was dissolved in THF (5mL), and the reaction solution was cooled to -10°C after nitrogen replacement three times, and DIBAL-H (8mL, 1.0M tetrahydrofuran solution) was added. Then the temperature of the reaction solution was raised to 0° C. for 6 hours. After the reaction was completed, add saturated potassium sodium tartrate aqueous solution (10 mL), then stir at room temperature for 1 hour, extract with ethyl acetate (20 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a light yellow solid LRQ -06-53, directly put into the next reaction without purification. HRMS (ESI) calcd for C10H16N3O2 + [ M +H]+: 210.1237 , found: 210.1242.
步骤5，将LRQ-06-53溶于DCM(10mL)后降温至0℃，依次加入四溴化碳(1.26g,3.79mmol)和三苯基膦(1.33g,5.06mmol)，室温反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到无色油状液体LRQ-06-55(261mg，两步反应收率38％)。1H NMR(800MHz,MeOH-d4)δ8.03(s,1H),5.03–4.97(m,2H),4.31–4.25(m,2H),3.92–3.90(m,2H),3.89(s,3H),3.20–3.15(m,2H),2.34–2.27(m,2H).HRMS(ESI)C10H15BrN3O+[M+H]+计算值：272.0393，实测值：272.0397。Step 5: Dissolve LRQ-06-53 in DCM (10mL) and cool down to 0°C, add carbon tetrabromide (1.26g, 3.79mmol) and triphenylphosphine (1.33g, 5.06mmol) in sequence, and react overnight at room temperature . After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1), to obtain colorless oily liquid LRQ-06-55 (261mg, two-step reaction yield 38%). 1 H NMR (800MHz, MeOH-d 4 )δ8.03(s,1H),5.03–4.97(m,2H),4.31–4.25(m,2H),3.92–3.90(m,2H),3.89(s ,3H), 3.20–3.15(m,2H), 2.34–2.27(m,2H).HRMS(ESI) Calcd. for C 10 H 15 BrN 3 O + [M+H]+: 272.0393, Found: 272.0397.
步骤6，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(191mg，1.48mmol)，LRQ-06-55(93mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(29mg，收率31％)。1H NMR(800MHz,CDCl3)δ7.97–7.94(m,1H),7.10(t,J＝7.8Hz,1H),7.03–6.99(m,1H),6.76(d,J＝7.9Hz,1H),4.27–4.21(m,2H),3.78–3.73(m,7H),3.52–3.47(m,2H),2.96–2.91(m,2H),2.87–2.82(m,2H),2.82–2.76(m,2H),2.74–2.69(m,2H),2.16–2.12(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ164.25,151.44,144.57,143.88,142.11,140.80,129.81,123.34,116.31,111.95,111.17,107.20,64.54,55.23,50.64,50.28,49.29,47.17,36.68,26.00,25.79,20.89,15.05.HRMS(ESI)C23H29N4O3 +[M+H]+计算值：409.2234，实测值：409.2238。HPLC:95.13％(λ＝254nm,tR＝12.08min)。Step 6, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (191mg, 1.48mmol) and LRQ-06-55 (93mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (29 mg, yield 31%). 1 H NMR (800MHz, CDCl 3 ) δ7.97–7.94(m,1H),7.10(t,J=7.8Hz,1H),7.03–6.99(m,1H),6.76(d,J=7.9Hz, 1H),4.27–4.21(m,2H),3.78–3.73(m,7H),3.52–3.47(m,2H),2.96–2.91(m,2H),2.87–2.82(m,2H),2.82– 2.76(m,2H),2.74–2.69(m,2H),2.16–2.12(m,2H),1.50(t,J＝7.0Hz,3H). 13 C NMR(201MHz,CDCl 3 )δ164.25,151.44, 144.57,143.88,142.11,140.80,129.81,123.34,116.31,111.95,111.17,107.20,64.54,55.23,50.64,50.28,49.29,47.17,36.68,26.00,25. 79, 20.89, 15.05. HRMS (ESI) C 23 H 29 N 4 O 3 + [M+H]+ calcd: 409.2234, found: 409.2238. HPLC: 95.13% (λ=254nm, tR =12.08min).
实施例43：化合物2-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(I-A43)(IHCH-5196)的制备
Example 43: Compound 2-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A43)(IHCH-5196)
将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-15(92mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50 mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(52mg，收率56％)。1H NMR(800MHz,CDCl3)δ7.38(s,1H),7.10(t,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),6.79–6.71(m,1H),4.24(q,J＝7.0Hz,2H),4.04–4.00(m,2H),3.69(s,2H),3.33(s,3H),2.86–2.81(m,2H),2.74–2.69(m,2H),2.67–2.62(m,2H),1.87–1.78(m,2H),1.67–1.60(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ156.31,151.21,148.94,144.56,143.90,133.88,129.85,123.26,111.84,111.14,107.14,64.51,56.83,51.76,50.54,50.27,27.08,26.18,24.41,20.93,15.06.HRMS(ESI)C21H27N4O4 +[M+H]+计算值：399.2027，实测值：399.2023。HPLC:98.26％(λ＝254nm,tR＝11.67min)。After LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), DIPEA (178 mg, 1.38 mmol) and LRQ-06-15 (92 mg, 0.35 mmol) were added sequentially, and reacted overnight at 100°C. Add water (10mL) to dilute after completion of the reaction, ethyl acetate (50 mL*3) extraction, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain a light yellow solid (52mg , yield 56%). 1 H NMR (800MHz, CDCl 3 ) δ7.38(s, 1H), 7.10(t, J=7.8Hz, 1H), 7.01(d, J=7.7Hz, 1H), 6.79–6.71(m, 1H) ,4.24(q,J＝7.0Hz,2H),4.04–4.00(m,2H),3.69(s,2H),3.33(s,3H),2.86–2.81(m,2H),2.74–2.69(m ,2H), 2.67–2.62(m,2H), 1.87–1.78(m,2H), 1.67–1.60(m,2H), 1.50(t, J＝7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ156.31, 151.21, 148.94, 144.56, 143.90, 133.88, 129.85, 123.26, 111.84, 111.14, 107.14, 64.51, 56.83, 51.76, 50.54, 50.27, 27.08, 26.1 8, 24.41, 20.93, 15.06. HRMS (ESI) C 21 H 27 N 4 O 4 + [M+H]+ calcd: 399.2027, found: 399.2023. HPLC: 98.26% (λ=254nm, tR =11.67min).
实施例44：化合物2-(3-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙基)-4-甲基-1,2,4-三嗪-3,5(2H,4H)-二酮(I-A44)(IHCH-5197)的制备
Example 44: Compound 2-(3-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)propyl)-4-methyl Preparation of -1,2,4-triazine-3,5(2H,4H)-dione (I-A44)(IHCH-5197)
步骤1，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-28(86mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(10mg，收率11％)。1H NMR(800MHz,MeOH-d4)δ7.41(s,1H),7.09(t,J＝7.8Hz,1H),7.02–6.99(m,1H),6.81(d,J＝7.8Hz,1H),4.21(q,J＝7.0Hz,2H),4.12–4.06(m,2H),3.68(s,2H),3.19(s,3H),2.90–2.82(m,2H),2.78–2.72(m,2H),2.72–2.66(m,2H),2.09–2.03(m,2H),1.44(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ158.04,151.64,150.58,145.84,145.36,134.97,130.80,124.46,112.76,112.09,108.96,65.64,55.68,51.42,51.31,50.92,27.04,26.36,21.60,15.28.HRMS(ESI)C20H25N4O4 +[M+H]+计算值：385.1870，实测值：385.1864。HPLC:98.94％(λ＝254nm,tR＝11.81min)。Step 1, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-06-28 (86mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (10 mg, yield 11%). 1 H NMR (800MHz, MeOH-d 4 )δ7.41(s, 1H), 7.09(t, J=7.8Hz, 1H), 7.02–6.99(m, 1H), 6.81(d, J=7.8Hz, 1H), 4.21(q, J=7.0Hz, 2H), 4.12–4.06(m, 2H), 3.68(s, 2H), 3.19(s, 3H), 2.90–2.82(m, 2H), 2.78–2.72 (m,2H),2.72–2.66(m,2H),2.09–2.03(m,2H),1.44(t,J＝7.0Hz,3H). 13 C NMR(201MHz,MeOH-d 4 )δ158.04,151.64 ,150.58,145.84,145.36,134.97,130.80,124.46,112.76,112.09,108.96,65.64,55.68,51.42,51.31,50.92,27.04,26.36,21.60,15.28.HRMS( ESI) C 20 H 25 N 4 O 4 + [M+H]+ calculated value: 385.1870, measured value: 385.1864. HPLC: 98.94% (λ=254nm, tR =11.81min).
实施例45：化合物1-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)-4,4-二甲基哌啶-2,6-二酮(I-A45)(IHCH-5191)的制备
Example 45: Compound 1-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-4,4- Preparation of Dimethylpiperidine-2,6-dione(I-A45)(IHCH-5191)
步骤1，将3,3-二甲基谷酰胺(1.00g，7.08mmol)溶于DMF(10mL)后，依次加入K2CO3(0.98g，7.08mmol)，1,4-二溴丁烷(4.59g，21.25mmol)，室温下反应过夜。反应完毕后加水(10mL)稀 释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到淡黄色油状液体LRQ-05-54(1.60g，收率82％)。1H NMR(800MHz,CDCl3)δ3.79(t,J＝7.3Hz,2H),3.41(t,J＝6.7Hz,2H),2.50(s,4H),1.88–1.81(m,2H),1.71–1.64(m,2H),1.07(s,6H).HRMS(ESI)C11H19BrNO2 +[M+H]+计算值：276.0594，实测值：276.0590。Step 1, after dissolving 3,3-dimethylglutamine (1.00g, 7.08mmol) in DMF (10mL), add K 2 CO 3 (0.98g, 7.08mmol), 1,4-dibromobutane in sequence (4.59g, 21.25mmol), react overnight at room temperature. After the reaction was complete, add water (10 mL) to dilute solution, extracted with ethyl acetate (50mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:4) , to obtain light yellow oily liquid LRQ-05-54 (1.60 g, yield 82%). 1 H NMR (800MHz, CDCl 3 ) δ3.79(t, J＝7.3Hz, 2H), 3.41(t, J＝6.7Hz, 2H), 2.50(s, 4H), 1.88–1.81(m, 2H) , 1.71–1.64 (m, 2H), 1.07 (s, 6H). HRMS (ESI) Calcd. for C11H19BrNO2 + [M+H]+ : 276.0594, found: 276.0590 .
步骤2，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-05-54(97mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(60mg，收率63％)。1H NMR(800MHz,MeOH-d4)δ7.12(t,J＝7.8Hz,1H),7.07–7.01(m,1H),6.84(d,J＝7.9Hz,1H),4.22(q,J＝7.0Hz,2H),3.84(s,2H),3.83–3.79(m,2H),3.07–2.99(m,2H),2.84–2.75(m,4H),2.56(s,4H),1.72–1.62(m,2H),1.62–1.54(m,2H),1.44(t,J＝7.0Hz,3H),1.06(s,6H).13C NMR(201MHz,MeOH-d4)δ174.20(2C),146.78,146.02,145.80,129.72,125.16,112.75,112.31,109.67,65.65,57.23,51.60,49.91,46.81(2C),39.43,30.00,27.69(2C),26.22,23.44,19.65,15.23.HRMS(ESI)C24H33N2O4 +[M+H]+计算值：413.2435，实测值：413.2433。HPLC:98.10％(λ＝254nm,tR＝12.32min)。Step 2, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-05-54 (97mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a light yellow solid (60 mg, yield 63%) was obtained. 1 H NMR (800MHz, MeOH-d 4 ) δ7.12(t, J=7.8Hz, 1H), 7.07–7.01(m, 1H), 6.84(d, J=7.9Hz, 1H), 4.22(q, J＝7.0Hz,2H),3.84(s,2H),3.83–3.79(m,2H),3.07–2.99(m,2H),2.84–2.75(m,4H),2.56(s,4H),1.72 –1.62 (m, 2H), 1.62 – 1.54 (m, 2H), 1.44 (t, J＝7.0Hz, 3H), 1.06 (s, 6H). 13 C NMR (201MHz, MeOH-d 4 ) δ174.20 (2C),146.78,146.02,145.80,129.72,125.16,112.75,112.31,109.67,65.65,57.23,51.60,49.91,46.81(2C),39.43,30.00,27.69(2C),26.22 ,23.44,19.65,15.23. HRMS (ESI) calcd for C24H33N2O4 + [M+H]+: 413.2435 , found : 413.2433. HPLC: 98.10% (λ=254nm, tR =12.32min).
实施例46：化合物8-(4-(8-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丁基)-8-氮杂螺[4.5]癸烷-7,9-二酮(I-A46)(IHCH-5192)的制备
Example 46: Compound 8-(4-(8-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)butyl)-8-aza Preparation of spiro[4.5]decane-7,9-dione (I-A46)(IHCH-5192)
步骤1，将3,3-四亚甲基戊二酰亚胺(1.00g，5.98mmol)溶于DMF(10mL)后，依次加入K2CO3(0.83g，5.98mmol)，1,4-二溴丁烷(3.87g，17.94mmol)，室温下反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:4)，得到淡黄色油状液体LRQ-05-55(1.60g，收率88％)。1H NMR(800MHz,CDCl3)δ3.79(t,J＝7.3Hz,2H),3.41(t,J＝6.7Hz,2H),2.59(s,4H),1.87–1.78(m,2H),1.74–1.63(m,6H),1.52–1.43(m,4H).HRMS(ESI)C13H21BrNO2 +[M+H]+计算值：302.0750，实测值：302.0752.Step 1, after dissolving 3,3-tetramethylene glutarimide (1.00g, 5.98mmol) in DMF (10mL), add K 2 CO 3 (0.83g, 5.98mmol), 1,4- Dibromobutane (3.87g, 17.94mmol) was reacted overnight at room temperature. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:4), to obtain light yellow oily liquid LRQ-05-55 (1.60g, yield 88%). 1 H NMR (800MHz, CDCl 3 ) δ3.79(t, J=7.3Hz, 2H), 3.41(t, J=6.7Hz, 2H), 2.59(s, 4H), 1.87–1.78(m, 2H) ,1.74–1.63(m,6H),1.52–1.43(m,4H).HRMS(ESI)C 13 H 21 BrNO 2 + [M+H]+calculated: 302.0750, found: 302.0752.
步骤2，将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-05-55(110mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体(42mg，收率41％)。1H NMR(800MHz,MeOH- d4)δ7.17(t,J＝7.9Hz,1H),7.12–7.06(m,1H),6.90(d,J＝7.8Hz,1H),4.31(s,2H),4.22(q,J＝7.0Hz,2H),3.84–3.78(m,2H),3.50–3.44(m,2H),3.23–3.18(m,2H),3.00–2.95(m,2H),2.64(s,4H),1.81–1.74(m,2H),1.74–1.68(m,4H),1.65–1.59(m,2H),1.53–1.47(m,4H),1.44(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ174.46(2C),146.85,146.04,145.83,129.74,125.15,112.75,112.30,109.67,65.66,57.25,51.61,49.93,45.39(2C),40.61,39.48,38.40(2C),26.26,25.15(2C),23.44,19.68,15.23.HRMS(ESI)C26H35N2O4 +[M+H]+计算值：439.2591，实测值：439.2587。HPLC:97.68％(λ＝254nm,tR＝12.64min)。Step 2, after dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol) and LRQ-05-55 (110mg, 0.35mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a pale yellow solid (42 mg, yield 41%). 1 H NMR (800MHz, MeOH- d 4 )δ7.17(t,J=7.9Hz,1H),7.12–7.06(m,1H),6.90(d,J=7.8Hz,1H),4.31(s,2H),4.22(q,J ＝7.0Hz,2H),3.84–3.78(m,2H),3.50–3.44(m,2H),3.23–3.18(m,2H),3.00–2.95(m,2H),2.64(s,4H), 1.81–1.74(m,2H),1.74–1.68(m,4H),1.65–1.59(m,2H),1.53–1.47(m,4H),1.44(t,J＝7.0Hz,3H). 13 C NMR(201MHz,MeOH-d 4 )δ174.46(2C),146.85,146.04,145.83,129.74,125.15,112.75,112.30,109.67,65.66,57.25,51.61,49.93,45.39(2C),40.6 1,39.48,38.40 (2C), 26.26, 25.15 (2C), 23.44, 19.68, 15.23. HRMS (ESI) Calculated for C 26 H 35 N 2 O 4 + [M+H]+: 439.2591, Found: 439.2587. HPLC: 97.68% (λ=254nm, tR =12.64min).
实施例47：化合物1-(2-(-乙氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)-1,3-二氢-2H-苯并[d]咪唑-2-酮(I-A47)(IHCH-5224)的制备
Example 47: Compound 1-(2-(-ethoxy-3,4-dihydrobenzofuro[2,3-c]pyridin-2(1H)-yl)ethyl)-1,3-di Preparation of Hydrogen-2H-Benzo[d]imidazol-2-one(I-A47)(IHCH-5224)
将LRQ-05-137(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，1-(2-溴乙基)-1,3-二氢-2H-苯并咪唑-2-酮(84mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(27mg，收率31％)。1H NMR(800MHz,CDCl3)δ9.68(s,1H),7.14–7.03(m,5H),7.00(d,J＝7.7Hz,1H),6.76(d,J＝7.9Hz,1H),4.25(q,J＝7.0Hz,2H),4.15–4.09(m,2H),3.85(s,2H),3.04–2.95(m,4H),2.75–2.69(m,2H),1.50(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ155.54,150.23,144.58,143.92,130.40,129.81,128.05,123.32,121.69,121.50,111.92,111.19,109.80,108.00,107.25,64.56,54.61,50.55,50.37,39.14,20.81,15.08.HRMS(ESI)C22H24N3O3 +[M+H]+计算值：378.1812，实测值：378.1815。HPLC:96.61％(λ＝254nm,tR＝11.84min)。After dissolving LRQ-05-137 (50mg, 0.23mmol) in DMF (8mL), add DIPEA (178mg, 1.38mmol), 1-(2-bromoethyl)-1,3-dihydro-2H-benzene Imidazol-2-one (84mg, 0.35mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (27 mg, yield 31%). 1 H NMR (800MHz, CDCl 3 ) δ9.68(s, 1H), 7.14–7.03(m, 5H), 7.00(d, J=7.7Hz, 1H), 6.76(d, J=7.9Hz, 1H) ,4.25(q,J＝7.0Hz,2H),4.15–4.09(m,2H),3.85(s,2H),3.04–2.95(m,4H),2.75–2.69(m,2H),1.50(t , J＝7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ155.54, 150.23, 144.58, 143.92, 130.40, 129.81, 128.05, 123.32, 121.69, 121.50, 111.92, 111.19, 109.80 ,108.00,107.25,64.56, 54.61, 50.55, 50.37 , 39.14, 20.81 , 15.08. HRMS (ESI) Calcd . for C22H24N3O3 + [M+H]+: 378.1812, found: 378.1815. HPLC: 96.61% (λ=254nm, tR =11.84min).
实施例48：化合物7-(4-(8-甲氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丁氧基)喹啉-2(1H)-酮(I-B1)的制备
Example 48: Compound 7-(4-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butoxy)quinone Preparation of Lin-2(1H)-one (I-B1)
步骤1、2、3：LRQ-04-165-Me的合成方法与专利US 5631265A19970520相同，LRQ-04-165-Me为黄色固体(三步反应收率17％)。1H NMR(800MHz,MeOH-d4)δ7.05(d,J＝7.9Hz,1H),6.97(t,J＝7.8Hz,1H),6.69–6.66(m,1H),4.34(s,2H),3.94(s,3H),3.51–3.47(m,2H),3.02–2.99(m,2H).HRMS(ESI)C12H15N2O+[M+H]+计算值：203.1179,实测值：203.1185。Steps 1, 2, 3: The synthesis method of LRQ-04-165-Me is the same as the patent US 5631265A19970520, and LRQ-04-165-Me is a yellow solid (the yield of the three-step reaction is 17%). 1 H NMR (800MHz, MeOH-d 4 )δ7.05(d, J=7.9Hz, 1H), 6.97(t, J=7.8Hz, 1H), 6.69–6.66(m, 1H), 4.34(s, 2H), 3.94(s,3H), 3.51–3.47(m,2H), 3.02–2.99(m,2H). HRMS(ESI) Calculated for C 12 H 15 N 2 O + [M+H] + : 203.1179 , measured value: 203.1185.
步骤4：将LRQ-04-165-Me(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(72mg，收率35％)。1H NMR(800MHz,MeOH-d4)δ7.88(d,J＝9.4Hz,1H),7.56(d,J＝8.7Hz,1H),7.04(d,J＝7.8Hz,1H),6.95(t,J＝7.8Hz,1H),6.90–6.87(m,1H),6.86(d,J＝2.3Hz,1H),6.66(d,J＝7.6Hz,1H),6.44(d,J＝9.4Hz,1H),4.21(s,2H),4.16(t,J＝5.9Hz,2H),3.94(s,3H),3.42–3.35(m,2H),3.18–3.11(m,2H),3.00(t,J＝5.8Hz,2H),2.03–1.98(m,2H),1.98–1.92(m,2H).13C NMR(201MHz,MeOH-d4)δ163.98,161.27,147.76,146.20,140.61,132.22,131.32,128.54,125.51,121.31,117.88,117.00,113.53,111.82,107.15,103.71,100.27,69.10,56.84,55.84,52.40,50.43,27.21,22.62,19.84.HRMS(ESI)C25H28N3O3 +[M+H]+计算值：418.2125，实测值：418.2126。HPLC:97.90％(λ＝254nm,tR＝11.51min)。Step 4: After LRQ-04-165-Me (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2( 1H)-ketone (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (72 mg, yield 35%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.88(d, J=9.4Hz, 1H), 7.56(d, J=8.7Hz, 1H), 7.04(d, J=7.8Hz, 1H), 6.95 (t,J=7.8Hz,1H),6.90–6.87(m,1H),6.86(d,J=2.3Hz,1H),6.66(d,J=7.6Hz,1H),6.44(d,J= 9.4Hz, 1H), 4.21(s, 2H), 4.16(t, J=5.9Hz, 2H), 3.94(s, 3H), 3.42–3.35(m, 2H), 3.18–3.11(m, 2H), 3.00(t,J=5.8Hz,2H),2.03–1.98(m,2H),1.98–1.92(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ163.98,161.27,147.76,146.20,140.61 ,132.22,131.32,128.54,125.51,121.31,117.88,117.00,113.53,111.82,107.15,103.71,100.27,69.10,56.84,55.84,52.40,50.43,27.21, 22.62, 19.84. HRMS (ESI) C 25 H 28 N 3 O 3 + [M+H] + calcd: 418.2125, found: 418.2126. HPLC: 97.90% (λ=254nm, tR =11.51min).
实施例49：化合物7-(4-(8-乙氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丁氧基)喹啉-2(1H)-酮(I-B2)的制备
Example 49: Compound 7-(4-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)butoxy)quinone Preparation of Lin-2(1H)-one (I-B2)
步骤1、2、3：LRQ-04-165-Et以2-乙氧基苯肼为原料，合成方法与专利US 5631265A19970520相同，LRQ-04-165-Et为黄色固体(三步反应收率16％)。1H NMR(800MHz,MeOH-d4)δ7.01(d,J＝7.8Hz,1H),6.90(t,J＝7.8Hz,1H),6.62(d,J＝7.6Hz,1H),4.18(q,J＝7.0Hz,2H),4.13(s,2H),3.30–3.24(m,2H),2.89–2.82(m,2H),1.47(t,J＝7.0Hz,3H).HRMS(ESI)C13H17N2O+[M+H]+计算值：217.1335,实测值：217.1337。Steps 1, 2, and 3: LRQ-04-165-Et uses 2-ethoxyphenylhydrazine as a raw material. The synthesis method is the same as that of the patent US 5631265A19970520. LRQ-04-165-Et is a yellow solid (the yield of the three-step reaction is 16 %). 1 H NMR (800MHz, MeOH-d 4 )δ7.01(d, J=7.8Hz, 1H), 6.90(t, J=7.8Hz, 1H), 6.62(d, J=7.6Hz, 1H), 4.18 (q,J=7.0Hz,2H),4.13(s,2H),3.30–3.24(m,2H),2.89–2.82(m,2H),1.47(t,J=7.0Hz,3H).HRMS( ESI) Calculated for C 13 H 17 N 2 O + [M+H] + : 217.1335, found: 217.1337.
步骤4：将LRQ-04-165-Et(105mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(36mg，收率17％)。1H NMR(800MHz,MeOH-d4)δ7.88(d,J＝9.4Hz,1H),7.57(d,J＝8.7Hz,1H),7.04(d,J＝7.8Hz,1H),6.95(t,J＝7.8Hz,1H),6.90–6.87(m,1H),6.86(d,J＝2.3Hz,1H),6.67(d,J＝7.6Hz,1H),6.44(d,J＝9.4Hz,1H),4.42–4.29(m,2H),4.20–4.16(m,4H),3.58–3.44(m,2H),3.35–3.32(m,1H),3.08–3.02(m,2H),2.08–2.02(m,2H),1.99–1.94(m,2H),1.47(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ163.68,160.60,146.94,141.94,140.79,131.12,129.86,126.99,125.49,121.26,116.30,115.24,111.71,107.11,104.68,104.49,100.22,68.98,64.75,56.89,52.42,50.45,27.20,22.60,19.85,15.31.HRMS(ESI)C26H30N3O3 +[M+H]+计算值：432.2282，实测值：432.2284。HPLC:97.97％(λ＝254nm,tR＝11.06min)。Step 4: After LRQ-04-165-Et (105 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy) quinoline-2 ( 1H)-ketone (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (36 mg, yield 17%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.88(d, J=9.4Hz, 1H), 7.57(d, J=8.7Hz, 1H), 7.04(d, J=7.8Hz, 1H), 6.95 (t,J=7.8Hz,1H),6.90–6.87(m,1H),6.86(d,J=2.3Hz,1H),6.67(d,J=7.6Hz,1H),6.44(d,J= 9.4Hz,1H),4.42–4.29(m,2H),4.20–4.16(m,4H),3.58–3.44(m,2H),3.35–3.32(m,1H),3.08–3.02(m,2H) ,2.08–2.02(m,2H),1.99–1.94(m,2H),1.47(t,J＝7.0Hz,3H). 13 C NMR(201MHz,MeOH-d 4 )δ163.68,160.60,146.94,141.94, 140.79,131.12,129.86,126.99,125.49,121.26,116.30,115.24,111.71,107.11,104.68,104.49,100.22,68.98,64.75,56.89,52.42,50.45, 27.20, 22.60, 19.85, 15.31. HRMS (ESI) C 26 H 30 N 3 O 3 + [M+H] + calcd: 432.2282, found: 432.2284. HPLC: 97.97% (λ=254nm, tR =11.06min).
实施例50：化合物7-(3-(8-甲氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙氧基)喹啉-2(1H)-酮(I-B3)的制备Example 50: Compound 7-(3-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)quinone Preparation of Lin-2(1H)-one (I-B3)
将LRQ-04-165-Me(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)喹啉-2(1H)-酮(208mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(98mg，收率50％)。1H NMR(800MHz,MeOH-d4)δ7.78(d,J＝9.4Hz,1H),7.48(d,J＝8.7Hz,1H),7.03(d,J＝7.8Hz,1H),6.94(t,J＝7.8Hz,1H),6.85–6.82(m,1H),6.80(d,J＝1.9Hz,1H),6.62–6.58(m,1H),6.43(d,J＝9.3Hz,1H),4.13(t,J＝5.9Hz,2H),3.92(s,3H),3.85(s,2H),3.02(s,2H),2.94–2.90(m,2H),2.89–2.84(m,2H),2.21–2.14(m,2H).13C NMR(201MHz,MeOH-d4)δ165.07,161.63,145.22,141.96,141.35,134.23,129.88,128.79,127.34,120.01,117.95,116.83,113.25,111.31,107.91,102.36,99.37,66.92,55.62,54.80,51.77,50.82,27.04,21.36.HRMS(ESI)C24H26N3O3 +[M+H]+计算值：404.1969，实测值：404.1970。HPLC:99.24％(λ＝ 254nm,tR＝11.88min)。After LRQ-04-165-Me (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)quinoline-2(1H)- Ketone (208 mg, 0.74 mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (98 mg, yield 50%). 1 H NMR (800MHz, MeOH-d 4 )δ7.78(d, J=9.4Hz, 1H), 7.48(d, J=8.7Hz, 1H), 7.03(d, J=7.8Hz, 1H), 6.94 (t,J=7.8Hz,1H),6.85–6.82(m,1H),6.80(d,J=1.9Hz,1H),6.62–6.58(m,1H),6.43(d,J=9.3Hz, 1H), 4.13(t, J=5.9Hz, 2H), 3.92(s, 3H), 3.85(s, 2H), 3.02(s, 2H), 2.94–2.90(m, 2H), 2.89–2.84(m ,2H),2.21–2.14(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ165.07,161.63,145.22,141.96,141.35,134.23,129.88,128.79,127.34,120.01,117.95,11 6.83,113.25, 111.31, 107.91, 102.36, 99.37, 66.92, 55.62, 54.80, 51.77, 50.82, 27.04, 21.36.HRMS(ESI)C 24 H 26 N 3 O 3 + [M+H] + Calculated: 404.1969, Found: 404.1970 . HPLC: 99.24% (λ= 254 nm, t R =11.88 min).
实施例51：化合物7-(3-(8-乙氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙氧基)喹啉-2(1H)-酮(I-B4)的制备
Example 51: Compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)quinone Preparation of Lin-2(1H)-one (I-B4)
将LRQ-04-165-Et(105mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)喹啉-2(1H)-酮(208mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(98mg，收率48％)。1H NMR(800MHz,MeOH-d4)δ7.75(d,J＝9.4Hz,1H),7.46(d,J＝8.7Hz,1H),7.03(d,J＝7.8Hz,1H),6.92(t,J＝7.8Hz,1H),6.83–6.80(m,1H),6.78(d,J＝2.2Hz,1H),6.58(d,J＝7.7Hz,1H),6.43(d,J＝9.4Hz,1H),4.19–4.14(m,2H),4.11(t,J＝6.1Hz,2H),3.83(s,2H),3.00(t,J＝5.5Hz,2H),2.92–2.87(m,2H),2.86(t,J＝5.8Hz,2H),2.21–2.10(m,2H),1.45(t,J＝7.0Hz,3H).13C NMR(201MHz,MeOH-d4)δ164.87,161.75,145.78,141.75,140.52,133.40,129.69,128.67,127.12,119.89,117.84,114.91,113.11,111.11,107.85,103.28,99.21,66.79,64.12,54.53,51.51,50.64,26.91,21.18,15.15.HRMS(ESI)C25H28N3O3 +[M+H]+计算值：418.2125，实测值：418.2124。HPLC:96.54％(λ＝254nm,tR＝12.22min)。After LRQ-04-165-Et (105mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)quinoline-2(1H)- Ketone (208 mg, 0.74 mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (98 mg, yield 48%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.75(d, J=9.4Hz, 1H), 7.46(d, J=8.7Hz, 1H), 7.03(d, J=7.8Hz, 1H), 6.92 (t,J=7.8Hz,1H),6.83–6.80(m,1H),6.78(d,J=2.2Hz,1H),6.58(d,J=7.7Hz,1H),6.43(d,J= 9.4Hz, 1H), 4.19–4.14(m, 2H), 4.11(t, J=6.1Hz, 2H), 3.83(s, 2H), 3.00(t, J=5.5Hz, 2H), 2.92–2.87( m,2H),2.86(t,J=5.8Hz,2H),2.21–2.10(m,2H),1.45(t,J=7.0Hz,3H). 13 C NMR(201MHz,MeOH-d 4 )δ164 .87,161.75,145.78,141.75,140.52,133.40,129.69,128.67,127.12,119.89,117.84,114.91,113.11,111.11,107.85,103.28,99.21,66.79, 64.12, 54.53, 51.51, 50.64, 26.91, 21.18, 15.15. HRMS ( ESI ) Calcd. for C25H28N3O3 + [M+H] + : 418.2125 , found : 418.2124. HPLC: 96.54% (λ=254nm, tR =12.22min).
实施例52：化合物7-(3-(8-甲氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-B5)的制备
Example 52: Compound 7-(3-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)- Preparation of 3,4-dihydroquinolin-2(1H)-one (I-B5)
将LRQ-04-165-Me(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)-3,4-二氢喹啉-2(1H)-酮(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(75mg，收率38％)。1H NMR(800MHz,MeOH-d4)δ7.04(d,J＝7.8Hz,1H),7.00(d,J＝8.3Hz,1H),6.95(t,J＝7.8Hz,1H),6.59(d,J＝7.7Hz,1H),6.51–6.47(m,1H),6.38(d,J＝2.3Hz,1H),3.99(t,J＝6.0Hz,2H),3.91(s,3H),3.87(s, 2H),3.03(t,J＝5.4Hz,2H),2.92–2.88(m,2H),2.87(t,J＝5.6Hz,2H),2.84(t,J＝7.6Hz,2H),2.56–2.49(m,2H),2.14–2.06(m,2H).13C NMR(201MHz,MeOH-d4)δ172.96,158.67,146.41,138.49,136.51,128.89,128.38,126.80,119.89,116.31,111.13,109.23,105.43,102.57,102.24,66.38,55.53,54.33,51.30,50.39,31.15,26.74,24.68,20.79.HRMS(ESI)C24H28N3O3 +[M+H]+计算值：406.2125，实测值：406.2123。HPLC:96.96％(λ＝254nm,tR＝12.32min)。After dissolving LRQ-04-165-Me (99mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)-3,4-dihydroquinone in sequence Lin-2(1H)-one (209mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (75 mg, yield 38%). 1 H NMR (800MHz, MeOH-d 4 )δ7.04(d, J=7.8Hz, 1H), 7.00(d, J=8.3Hz, 1H), 6.95(t, J=7.8Hz, 1H), 6.59 (d, J=7.7Hz, 1H), 6.51–6.47(m, 1H), 6.38(d, J=2.3Hz, 1H), 3.99(t, J=6.0Hz, 2H), 3.91(s, 3H) ,3.87(s, 2H), 3.03(t, J=5.4Hz, 2H), 2.92–2.88(m, 2H), 2.87(t, J=5.6Hz, 2H), 2.84(t, J=7.6Hz, 2H), 2.56– 2.49(m,2H),2.14–2.06(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ172.96,158.67,146.41,138.49,136.51,128.89,128.38,126.80,119.89,116.31,111 .13,109.23 ,105.43,102.57,102.24,66.38,55.53,54.33,51.30,50.39,31.15,26.74,24.68,20.79.HRMS(ESI)C 24 H 28 N 3 O 3 + [M+H] + calculated value: 406.2125, measured Value: 406.2123. HPLC: 96.96% (λ=254nm, tR =12.32min).
实施例53：化合物7-(3-(8-乙氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-B6)的制备
Example 53: Compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl)propoxy)- Preparation of 3,4-dihydroquinolin-2(1H)-one (I-B6)
将LRQ-04-165-Et(105mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)-3,4-二氢喹啉-2(1H)-酮(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(84mg，收率41％)。1H NMR(800MHz,CDCl3)δ8.18(s,1H),8.09(s,1H),7.07(d,J＝7.9Hz,1H),7.02(d,J＝8.3Hz,1H),6.98(t,J＝7.8Hz,1H),6.61(d,J＝7.7Hz,1H),6.54–6.50(m,1H),6.33–6.29(m,1H),4.19(q,J＝7.0Hz,2H),4.02(t,J＝6.3Hz,2H),3.76(s,2H),2.93(t,J＝5.4Hz,2H),2.87(t,J＝7.5Hz,2H),2.83(t,J＝5.5Hz,2H),2.81(t,J＝7.2Hz,2H),2.62–2.58(m,2H),2.10–2.05(m,2H),1.46(t,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ171.78,158.69,145.27,138.24,136.41,128.78,128.56,126.55,122.29,119.92,115.92,110.94,108.90,102.89,102.29,66.44,63.73,54.11,51.18,50.51,31.23,29.84,27.26,24.72,15.19.HRMS(ESI)C25H30N3O3 +[M+H]+计算值：420.2282，实测值：420.2283。HPLC:99.77％(λ＝254nm,tR＝12.32min)。After LRQ-04-165-Et (105mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)-3,4-dihydroquinone were added successively Lin-2(1H)-one (209mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (84 mg, yield 41%). 1 H NMR (800MHz, CDCl 3 ) δ8.18(s, 1H), 8.09(s, 1H), 7.07(d, J=7.9Hz, 1H), 7.02(d, J=8.3Hz, 1H), 6.98 (t,J=7.8Hz,1H),6.61(d,J=7.7Hz,1H),6.54–6.50(m,1H),6.33–6.29(m,1H),4.19(q,J=7.0Hz, 2H), 4.02(t, J=6.3Hz, 2H), 3.76(s, 2H), 2.93(t, J=5.4Hz, 2H), 2.87(t, J=7.5Hz, 2H), 2.83(t, J＝5.5Hz, 2H), 2.81(t, J＝7.2Hz, 2H), 2.62–2.58(m, 2H), 2.10–2.05(m, 2H), 1.46(t, J＝7.0Hz, 3H). 13 C NMR (201MHz, CDCl 3 ) δ171.78, 158.69, 145.27, 138.24, 136.41, 128.78, 128.56, 126.55, 122.29, 119.92, 115.92, 110.94, 108.90, 102.89, 102.2 9,66.44,63.73,54.11,51.18,50.51,31.23 , 29.84, 27.26, 24.72, 15.19. HRMS (ESI) Calcd. for C25H30N3O3 + [ M +H] + : 420.2282, found: 420.2283. HPLC: 99.77% (λ=254nm, tR =12.32min).
实施例54：化合物3-(反式-4-(2-(8-甲氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)乙基)环己基)-1,1-二甲基脲(I-B7)的制备
Example 54: Compound 3-(trans-4-(2-(8-methoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl ) ethyl) cyclohexyl) -1, the preparation of 1-dimethylurea (I-B7)
将LRQ-04-165-Me(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(13mg，收率27％)。1H NMR(800MHz,MeOH-d4)δ 7.03–6.98(m,1H),6.91(t,J＝7.8Hz,1H),6.62(d,J＝7.7Hz,1H),3.93(s,3H),3.84–3.74(m,2H),3.54–3.46(m,1H),3.02–2.96(m,2H),2.91–2.82(m,8H),2.80–2.70(m,2H),1.94–1.88(m,2H),1.87–1.82(m,2H),1.62–1.55(m,2H),1.35–1.31(m,1H),1.30–1.26(m,2H),1.16–1.07(m,2H).13C NMR(201MHz,MeOH-d4)δ153.70,144.70,134.33,129.52,128.07,120.52,115.01,111.67,108.14,56.78,55.75,52.52,51.37,51.18,36.72,36.43(2C),35.41,34.29(2C),33.35(2C),21.71.HRMS(ESI)C23H35N4O2 +[M+H]+计算值：399.2755，实测值：399.2752。HPLC:97.46％(λ＝254nm,tR＝11.33min)。After dissolving LRQ-04-165-Me (24mg, 0.12mmol) in DMF (8mL), DIPEA (45mg, 0.35mmol) and LRQ-04-152 (47mg, 0.17mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), a white solid was obtained (13 mg, yield 27%). 1 H NMR (800MHz, MeOH-d 4 )δ 7.03–6.98(m,1H),6.91(t,J=7.8Hz,1H),6.62(d,J=7.7Hz,1H),3.93(s,3H),3.84–3.74(m,2H),3.54 –3.46(m,1H),3.02–2.96(m,2H),2.91–2.82(m,8H),2.80–2.70(m,2H),1.94–1.88(m,2H),1.87–1.82(m, 2H),1.62–1.55(m,2H),1.35–1.31(m,1H),1.30–1.26(m,2H),1.16–1.07(m,2H). 13 C NMR(201MHz,MeOH-d 4 ) δ153.70,144.70,134.33,129.52,128.07,120.52,115.01,111.67,108.14,56.78,55.75,52.52,51.37,51.18,36.72,36.43(2C),35.41,34.29 (2C),33.35(2C),21.71.HRMS (ESI) Calcd . for C23H35N4O2 + [M+H] + : 399.2755 , found: 399.2752. HPLC: 97.46% (λ=254nm, tR =11.33min).
实施例55：化合物3-(反式-4-(2-(8-乙氧基-1,3,4,9-四氢-2H-吡啶[3,4-b]吲哚-2-基)乙基)环己基)-1,1-二甲基脲(I-B8)的制备
Example 55: Compound 3-(trans-4-(2-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyridin[3,4-b]indol-2-yl ) ethyl) cyclohexyl) -1, the preparation of 1-dimethylurea (I-B8)
将LRQ-04-165-Et(26mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析(甲醇/二氯甲烷＝1:10)分离纯化，得到白色固体(5mg，收率10％)。1H NMR(800MHz,CDCl3)δ7.00(d,J＝7.9Hz,1H),6.94(t,J＝7.8Hz,1H),6.57(d,J＝7.7Hz,1H),4.13(q,J＝7.0Hz,2H),4.01(s,2H),3.56–3.49(m,1H),3.14–3.06(m,2H),2.92–2.87(m,2H),2.85(s,6H),2.82–2.74(m,2H),2.00–1.91(m,2H),1.74–1.66(m,2H),1.63–1.53(m,2H),1.42(t,J＝7.0Hz,3H),1.27–1.24(m,1H),1.08–0.99(m,4H).13C NMR(201MHz,CDCl3)δ157.91,145.41,133.63,127.94,126.88,120.03,110.77,107.55,103.26,63.76,55.16,54.20,50.38,49.75,36.24(2C),35.21,33.79(2C),31.90(2C),29.75,20.98,15.07.HRMS(ESI)C24H37N4O2 +[M+H]+计算值：413.2911，实测值：413.2913。HPLC:97.72％(λ＝254nm,tR＝11.31min)。After LRQ-04-165-Et (26 mg, 0.12 mmol) was dissolved in DMF (8 mL), DIPEA (45 mg, 0.35 mmol) and LRQ-04-152 (47 mg, 0.17 mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol/dichloromethane = 1:10) separation and purification to obtain a white solid (5 mg, yield 10%). 1 H NMR (800MHz, CDCl 3 ) δ7.00(d, J=7.9Hz, 1H), 6.94(t, J=7.8Hz, 1H), 6.57(d, J=7.7Hz, 1H), 4.13(q ,J＝7.0Hz,2H),4.01(s,2H),3.56–3.49(m,1H),3.14–3.06(m,2H),2.92–2.87(m,2H),2.85(s,6H), 2.82–2.74(m,2H),2.00–1.91(m,2H),1.74–1.66(m,2H),1.63–1.53(m,2H),1.42(t,J＝7.0Hz,3H),1.27– 1.24(m,1H),1.08–0.99(m,4H). 13 C NMR(201MHz,CDCl 3 )δ157.91,145.41,133.63,127.94,126.88,120.03,110.77,107.55,103.26,63.76,55.16, 54.20,50.38 , 49.75, 36.24(2C), 35.21, 33.79(2C), 31.90(2C), 29.75, 20.98, 15.07.HRMS(ESI) Calcd for C 24 H 37 N 4 O 2 + [M+H] + : 413.2911, Found value: 413.2913. HPLC: 97.72% (λ=254nm, tR =11.31min).
实施例56：化合物1-((8-甲氧基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)甲基)环己烷-1-醇(I-B9)(IHCH-5229)的制备
Example 56: Compound 1-((8-Methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)methyl)cyclohexane Preparation of -1-alcohol (I-B9) (IHCH-5229)
将LRQ-05-165-Me(50mg,0.25mmol)溶于无水乙醇(10mL)，加入亚甲基环己烷氧化物(138mg,1.25mmol)后，升温至60℃反应过夜。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯 化(甲醇/二氯甲烷＝1:10)，得到淡黄色固体IHCH-5229(5mg，收率6％)。1H NMR(800MHz,CDCl3)δ8.02(s,1H),7.10(d,J＝7.9Hz,1H),7.02(t,J＝7.8Hz,1H),6.65–6.61(m,1H),3.94(s,3H),3.91(s,2H),3.08–3.00(m,2H),2.87–2.79(m,2H),2.59(s,2H),1.70–1.65(m,2H),1.63–1.54(m,3H),1.50–1.45(m,2H),1.40–1.37(m,2H),1.31–1.29(m,1H).13C NMR(201MHz,CDCl3)δ146.02,136.02,128.45,126.19,120.04,114.41,111.04,102.07,70.64,66.22,55.48,53.53,53.01,36.73(2C),26.02,22.28(2C),21.13.HRMS(ESI)C19H27N2O2 +[M+H]+计算值：315.2067，实测值：315.2069。HPLC:95.97％(λ＝254nm,tR＝11.90min)。LRQ-05-165-Me (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), methylenecyclohexane oxide (138 mg, 1.25 mmol) was added, and the temperature was raised to 60° C. to react overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. (methanol/dichloromethane=1:10) to obtain light yellow solid IHCH-5229 (5 mg, yield 6%). 1 H NMR (800MHz, CDCl 3 ) δ8.02(s, 1H), 7.10(d, J=7.9Hz, 1H), 7.02(t, J=7.8Hz, 1H), 6.65–6.61(m, 1H) ,3.94(s,3H),3.91(s,2H),3.08–3.00(m,2H),2.87–2.79(m,2H),2.59(s,2H),1.70–1.65(m,2H),1.63 –1.54(m,3H),1.50–1.45(m,2H),1.40–1.37(m,2H),1.31–1.29(m,1H). 13 C NMR(201MHz,CDCl 3 )δ146.02,136.02,128.45, 126.19,120.04,114.41, 111.04, 102.07,70.64,66.22,55.48,53.53, 53.01,36.73 (2C), 26.02,22.28 (2C), 21.13.HRMS (ESI) C 19 H 27 N 2 O 2 + [m + [m + [m + [m + [m + [m + [m + [m + [m + [m + [m + [m + [m + [ m + H] + Calculated: 315.2067, Found: 315.2069. HPLC: 95.97% (λ=254nm, tR =11.90min).
实施例57：化合物3-(3-(2-(8-甲氧基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)乙基)环丁基)-1,1-二甲基脲(I-B10)(IHCH-5226)的制备
Example 57: Compound 3-(3-(2-(8-methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)ethan base) cyclobutyl) -1,1-dimethylurea (I-B10) (IHCH-5226) preparation
将LRQ-05-165-Me(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-04(87mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(13mg，收率14％)。1H NMR(800MHz,CDCl3)δ8.70(d,J＝67.5Hz,1H),7.09–7.01(m,1H),7.01–6.93(m,1H),6.62–6.57(m,1H),4.64–4.57(m,1H),4.39–4.09(m,1H),3.95–3.86(m,3H),3.82–3.74(m,2H),2.98–2.90(m,2H),2.89–2.84(m,6H),2.84–2.78(m,2H),2.61–2.53(m,2H),2.52–2.43(m,1H),2.22–1.83(m,3H),1.84–1.76(m,1H),1.77–1.69(m,1H),1.49–1.41(m,1H).HRMS(ESI)C21H31N4O2 +[M+H]+计算值：371.2442，实测值：371.2443。HPLC:95.02％(λ＝254nm,tR＝11.25min)。After dissolving LRQ-05-165-Me (50mg, 0.23mmol) in DMF (8mL), DIPEA (178mg, 1.38mmol) and LRQ-06-04 (87mg, 0.35mmol) were added successively, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (13 mg, yield 14%). 1 H NMR (800MHz, CDCl 3 ) δ8.70(d, J=67.5Hz, 1H), 7.09–7.01(m, 1H), 7.01–6.93(m, 1H), 6.62–6.57(m, 1H), 4.64–4.57(m,1H),4.39–4.09(m,1H),3.95–3.86(m,3H),3.82–3.74(m,2H),2.98–2.90(m,2H),2.89–2.84(m ,6H),2.84–2.78(m,2H),2.61–2.53(m,2H),2.52–2.43(m,1H),2.22–1.83(m,3H),1.84–1.76(m,1H),1.77 –1.69 (m, 1H), 1.49 – 1.41 (m, 1H). HRMS (ESI) Calculated for C 21 H 31 N 4 O 2 + [M+H]+: 371.2442, Found: 371.2443. HPLC: 95.02% (λ=254nm, tR =11.25min).
实施例58：化合物3-(3-(2-(8-乙氧基-1,3,4,9-四氢-2H-吡啶并[3,4-b]吲哚-2-基)乙基)环丁基)-1,1-二甲基脲(I-B11)(IHCH-5227)的制备
Example 58: Compound 3-(3-(2-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)ethan base) cyclobutyl) -1,1-dimethylurea (I-B11) (IHCH-5227) preparation
将LRQ-05-165-Et(50mg，0.23mmol)溶于DMF(8mL)后，依次加入DIPEA(178mg，1.38mmol)，LRQ-06-04(87mg，0.35mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离 纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(20mg，收率23％)。1H NMR(800MHz,CDCl3)δ7.01–6.97(m,1H),6.96(t,J＝7.7Hz,1H),6.60–6.56(m,1H),5.14–4.79(m,1H),4.36–4.25(m,2H),4.13–4.09(m,2H),3.34–3.26(m,2H),3.02–2.94(m,2H),2.91–2.81(m,8H),2.46–2.19(m,2H),2.07–2.02(m,1H),2.00–1.94(m,2H),1.85–1.76(m,1H),1.61–1.55(m,1H),1.42(t,J＝3.5Hz,3H).HRMS(ESI)C22H33N4O2 +[M+H]+计算值：385.2598，实测值：385.2595。HPLC:95.17％(λ＝254nm,tR＝11.25min)。After dissolving LRQ-05-165-Et (50mg, 0.23mmol) in DMF (8mL), DIPEA (178mg, 1.38mmol) and LRQ-06-04 (87mg, 0.35mmol) were added successively, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated by silica gel column chromatography Purification (methanol/dichloromethane=1:10) gave a reddish-brown solid (20 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 )δ7.01–6.97(m,1H),6.96(t,J=7.7Hz,1H),6.60–6.56(m,1H),5.14–4.79(m,1H), 4.36–4.25(m,2H),4.13–4.09(m,2H),3.34–3.26(m,2H),3.02–2.94(m,2H),2.91–2.81(m,8H),2.46–2.19(m ,2H),2.07–2.02(m,1H),2.00–1.94(m,2H),1.85–1.76(m,1H),1.61–1.55(m,1H),1.42(t,J＝3.5Hz,3H ). HRMS (ESI) calcd for C22H33N4O2 + [M+H]+ : 385.2598 , found: 385.2595 . HPLC: 95.17% (λ=254nm, tR =11.25min).
实施例59：化合物7-(4-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丁氧基)喹啉-2(1H)-酮(I-C1)的制备
Example 59: Compound 7-(4-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)quinoline-2 Preparation of (1H)-ketone (I-C1)
步骤1-3：LRQ-05-03的合成方法与专利WO2004099212A1相同，LRQ-05-03为红棕色固体(三步反应收率57％)。1H NMR(800MHz,MeOH-d4)δ7.03(t,J＝7.9Hz,1H),6.93(d,J＝8.2Hz,1H),6.53(d,J＝7.7Hz,1H),6.26–6.21(m,1H),4.14(s,2H),4.04–4.00(m,2H),3.90(s,3H),3.31–3.30(m,2H).HRMS(ESI)C12H15N2O+[M+H]+计算值：203.1179,实测值：203.1174。Step 1-3: The synthesis method of LRQ-05-03 is the same as the patent WO2004099212A1, and LRQ-05-03 is a reddish-brown solid (the yield of the three-step reaction is 57%). 1 H NMR (800MHz, MeOH-d 4 )δ7.03(t, J=7.9Hz, 1H), 6.93(d, J=8.2Hz, 1H), 6.53(d, J=7.7Hz, 1H), 6.26 –6.21(m,1H),4.14(s,2H),4.04–4.00(m,2H),3.90(s,3H),3.31–3.30(m,2H).HRMS(ESI)C 12 H 15 N 2 O + [M+H] + calculated: 203.1179, found: 203.1174.
步骤4：将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(59mg，收率29％)。1H NMR(800MHz,CDCl3)δ12.06(s,1H),7.71(d,J＝9.4Hz,1H),7.43(d,J＝8.5Hz,1H),7.07(t,J＝7.9Hz,1H),6.90(d,J＝8.1Hz,1H),6.84–6.77(m,2H),6.59–6.46(m,2H),6.30(s,1H),4.11(t,J＝6.1Hz,2H),4.07(t,J＝5.5Hz,2H),3.94(s,3H),3.85(s,2H),3.00(t,J＝5.4Hz,2H),2.65(t,J＝7.2Hz,2H),1.94–1.87(m,2H),1.83–1.79(m,2H).13C NMR(201MHz,MeOH-d4)δ164.55,161.52,152.95,141.40,140.14,137.62,132.17,129.35,121.75,118.69,117.57,114.48,112.88,102.48,100.31,98.92,94.21,68.04,57.33,55.42,51.48,50.59,41.76,27.06,23.57.HRMS(ESI)C25H28N3O3 +[M+H]+计算值：418.2125，实测值：418.2120。HPLC:97.08％(λ＝254nm,tR＝11.84min)。Step 4: After dissolving LRQ-05-03 (99mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (59 mg, yield 29%). 1 H NMR (800MHz, CDCl3) δ12.06(s, 1H), 7.71(d, J=9.4Hz, 1H), 7.43(d, J=8.5Hz, 1H), 7.07(t, J=7.9Hz, 1H), 6.90(d, J＝8.1Hz, 1H), 6.84–6.77(m, 2H), 6.59–6.46(m, 2H), 6.30(s, 1H), 4.11(t, J＝6.1Hz, 2H ),4.07(t,J=5.5Hz,2H),3.94(s,3H),3.85(s,2H),3.00(t,J=5.4Hz,2H),2.65(t,J=7.2Hz,2H ),1.94–1.87(m,2H),1.83–1.79(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ164.55,161.52,152.95,141.40,140.14,137.62,132.17,129.35,121.75,118 .69 ,117.57,114.48,112.88,102.48,100.31,98.92,94.21,68.04,57.33,55.42,51.48,50.59,41.76,27.06,23.57.HRMS(ESI)C 25 H 28 N 3 O 3 + [M+H ] + Calculated value: 418.2125, measured value: 418.2120. HPLC: 97.08% (λ=254nm, tR =11.84min).
实施例60：化合物7-(4-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丁氧基)-3,4-二氢喹啉-2(1H)- 酮(I-C2)的制备
Example 60: Compound 7-(4-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)-3,4 -Dihydroquinoline-2(1H)- Preparation of Ketones (I-C2)
将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)-3,4-二氢喹啉-2(1H)-酮(220mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到红棕色固体(64mg，收率31％)。1H NMR(800MHz,CDCl3)δ8.04(s,1H),7.07(t,J＝7.9Hz,1H),7.03(d,J＝8.3Hz,1H),6.90(d,J＝8.1Hz,1H),6.55–6.49(m,2H),6.32–6.27(m,2H),4.06(t,J＝5.6Hz,2H),4.00–3.91(m,5H),3.83(s,2H),2.98(t,J＝5.6Hz,2H),2.88(t,J＝7.5Hz,2H),2.66–2.55(m,4H),1.89–1.81(m,2H),1.80–1.74(m,2H).13C NMR(201MHz,CDCl3)δ171.76,158.77,153.07,138.26,137.59,132.91,128.81,121.51,118.79,115.91,108.82,102.35,102.34,100.20,93.92,67.97,57.38,55.50,51.57,50.71,42.13,31.24,27.21,24.74,23.83.HRMS(ESI)C25H30N3O3 +[M+H]+计算值：420.2282，实测值：420.2276。HPLC:96.64％(λ＝254nm,tR＝11.86min)。After LRQ-05-03 (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)-3,4-dihydroquinoline- 2(1H)-Kone (220mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a reddish-brown solid (64 mg, yield 31%). 1 H NMR (800MHz, CDCl 3 ) δ8.04(s, 1H), 7.07(t, J=7.9Hz, 1H), 7.03(d, J=8.3Hz, 1H), 6.90(d, J=8.1Hz ,1H),6.55–6.49(m,2H),6.32–6.27(m,2H),4.06(t,J＝5.6Hz,2H),4.00–3.91(m,5H),3.83(s,2H), 2.98(t, J＝5.6Hz, 2H), 2.88(t, J＝7.5Hz, 2H), 2.66–2.55(m, 4H), 1.89–1.81(m, 2H), 1.80–1.74(m, 2H) . 13 C NMR (201MHz, CDCl 3 ) δ171.76, 158.77, 153.07, 138.26, 137.59, 132.91, 128.81, 121.51, 118.79, 115.91, 108.82, 102.35, 102.34, 100.20, 93. 92,67.97,57.38,55.50,51.57,50.71, 42.13, 31.24, 27.21 , 24.74, 23.83. HRMS (ESI) Calcd. for C25H30N3O3 + [ M +H] + : 420.2282, found: 420.2276. HPLC: 96.64% (λ=254nm, tR =11.86min).
实施例61：化合物7-(3-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丙氧基)喹啉-2(1H)-酮(I-C3)的制备
Example 61: Compound 7-(3-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)propoxy)quinoline-2 Preparation of (1H)-ketone (I-C3)
将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)喹啉-2(1H)-酮(208mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(53mg，收率27％)。1H NMR(800MHz,MeOH-d4)δ7.77(d,J＝9.3Hz,1H),7.48(d,J＝8.7Hz,1H),7.09(t,J＝8.0Hz,1H),6.93(d,J＝8.1Hz,1H),6.89–6.83(m,1H),6.81(d,J＝2.4Hz,1H),6.56(d,J＝7.7Hz,1H),6.47(d,J＝9.4Hz,1H),6.28(s,3H),4.16(t,J＝6.1Hz,2H),4.11(t,J＝5.7Hz,2H),3.95(s,3H),3.90(s,2H),3.07(t,J＝5.6Hz,2H),2.82(t,J＝7.4Hz,2H),2.19–2.10(m,2H).13C NMR(201MHz,MeOH-d4)δ164.75,161.64,153.12,141.60,140.33,137.82,132.38,129.54,121.94,118.87,117.72,114.74,112.98,102.66,100.50,99.14,94.34,66.51,55.54,54.55,51.75,50.88,42.02,26.95.HRMS(ESI)C24H26N3O3 +[M+H]+计算值：404.1969，实测值：404.1972。 HPLC:99.27％(λ＝254nm,tR＝11.56min)。After LRQ-05-03 (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one ( 208mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (53 mg, yield 27%). 1 H NMR (800MHz, MeOH-d 4 ) δ7.77(d, J=9.3Hz, 1H), 7.48(d, J=8.7Hz, 1H), 7.09(t, J=8.0Hz, 1H), 6.93 (d,J=8.1Hz,1H),6.89–6.83(m,1H),6.81(d,J=2.4Hz,1H),6.56(d,J=7.7Hz,1H),6.47(d,J= 9.4Hz, 1H), 6.28(s, 3H), 4.16(t, J=6.1Hz, 2H), 4.11(t, J=5.7Hz, 2H), 3.95(s, 3H), 3.90(s, 2H) ,3.07(t,J=5.6Hz,2H),2.82(t,J=7.4Hz,2H),2.19–2.10(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ164.75,161.64,153.12 ,141.60,140.33,137.82,132.38,129.54,121.94,118.87,117.72,114.74,112.98,102.66,100.50,99.14,94.34,66.51,55.54,54.55,51.75, 50.88, 42.02, 26.95. HRMS (ESI) C 24 H 26 N 3 O 3 + [M+H] + calcd: 404.1969, found: 404.1972. HPLC: 99.27% (λ=254nm, tR =11.56min).
实施例62：化合物7-(3-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-C4)的制备
Example 62: Compound 7-(3-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)propoxy)-3,4 -Preparation of dihydroquinolin-2(1H)-ketone (I-C4)
将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)-3,4-二氢喹啉-2(1H)-酮(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(65mg，收率33％)。1H NMR(800MHz,CDCl3)δ8.26(s,1H),7.08(t,J＝7.9Hz,1H),7.03(d,J＝8.3Hz,1H),6.90(d,J＝8.1Hz,1H),6.56–6.49(m,2H),6.36–6.32(m,1H),6.31(s,1H),4.07(t,J＝5.5Hz,2H),4.03(t,J＝6.1Hz,2H),3.94(s,3H),3.86(s,2H),3.01(t,J＝5.3Hz,2H),2.88(t,J＝7.5Hz,2H),2.75(t,J＝7.0Hz,2H),2.60(t,J＝7.5Hz,2H),2.09–2.02(m,2H).13C NMR(201MHz,CDCl3)δ171.91,158.69,153.06,138.28,137.56,132.66,128.79,121.59,118.75,115.96,108.77,102.36,102.36,100.19,94.01,66.18,55.49,54.27,51.56,50.79,42.08,31.21,27.12,24.71.HRMS(ESI)C24H28N3O3 +[M+H]+计算值：406.2125，实测值：406.2131。HPLC:97.30％(λ＝254nm,tR＝11.64min)。After LRQ-05-03 (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)-3,4-dihydroquinoline- 2(1H)-ketone (209mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (65 mg, yield 33%). 1 H NMR (800MHz, CDCl 3 ) δ8.26(s, 1H), 7.08(t, J=7.9Hz, 1H), 7.03(d, J=8.3Hz, 1H), 6.90(d, J=8.1Hz ,1H),6.56–6.49(m,2H),6.36–6.32(m,1H),6.31(s,1H),4.07(t,J＝5.5Hz,2H),4.03(t,J＝6.1Hz, 2H), 3.94(s, 3H), 3.86(s, 2H), 3.01(t, J=5.3Hz, 2H), 2.88(t, J=7.5Hz, 2H), 2.75(t, J=7.0Hz, 2H), 2.60(t, J=7.5Hz, 2H), 2.09–2.02(m, 2H). 13 C NMR (201MHz, CDCl 3 ) δ171.91, 158.69, 153.06, 138.28, 137.56, 132.66, 128.79, 121.59, 118.75 ,115.96,108.77,102.36,102.36,100.19,94.01,66.18,55.49,54.27,51.56,50.79,42.08,31.21,27.12,24.71.HRMS(ESI)C 24 H 28 N 3 O 3 + [M+H ] + Calculated value: 406.2125, measured value: 406.2131. HPLC: 97.30% (λ=254nm, tR =11.64min).
实施例63：化合物(E)-7-((4-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丁-2-烯-1-基)氧基)喹啉-2(1H)-酮(I-C5)的制备
Example 63: Compound (E)-7-((4-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)butan-2 Preparation of -en-1-yl)oxy)quinolin-2(1H)-one (I-C5)
将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，(E)-7-(4-溴代丁-2-烯-1-基)氧基)喹啉-2(1H)-酮(217mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(47mg，收率23％)。1H NMR(800MHz,MeOH-d4)δ7.73–7.70(m,1H),7.44(d,J＝8.7Hz,1H),7.03(t,J＝7.9Hz,1H),6.86(d,J＝8.1Hz,1H),6.83–6.81(m,1H),6.78(d,J＝2.3Hz,1H),6.50(d,J＝7.7Hz,1H),6.44(d,J＝9.4Hz,1H),6.25–6.23(m,1H),5.99–5.90(m,2H),4.62(d,J＝4.6Hz,2H),4.03(t,J＝5.7Hz,2H),3.89(s,3H),3.80 (s,2H),3.24(d,J＝5.5Hz,2H),2.98–2.94(m,2H).13C NMR(201MHz,MeOH-d4)δ164.52,160.95,152.97,141.33,140.13,137.65,132.11,130.28,129.41,129.21,121.78,118.70,117.86,114.65,112.98,102.48,100.33,99.38,94.26,68.27,59.34,55.42,51.48,50.22,41.82.HRMS(ESI)C25H26N3O3 +[M+H]+计算值：416.1969，实测值：416.1971。HPLC:98.09％(λ＝254nm,tR＝11.75min)。After LRQ-05-03 (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), (E)-7-(4-bromobut-2-en-1-yl )oxy)quinolin-2(1H)-one (217mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (47 mg, yield 23%). 1 H NMR (800MHz, MeOH-d 4 )δ7.73–7.70(m, 1H), 7.44(d, J=8.7Hz, 1H), 7.03(t, J=7.9Hz, 1H), 6.86(d, J＝8.1Hz, 1H), 6.83–6.81(m, 1H), 6.78(d, J＝2.3Hz, 1H), 6.50(d, J＝7.7Hz, 1H), 6.44(d, J＝9.4Hz, 1H),6.25–6.23(m,1H),5.99–5.90(m,2H),4.62(d,J＝4.6Hz,2H),4.03(t,J＝5.7Hz,2H),3.89(s,3H ),3.80 (s,2H),3.24(d,J＝5.5Hz,2H),2.98–2.94(m,2H). 13 C NMR(201MHz,MeOH-d 4 )δ164.52,160.95,152.97,141.33,140.13,137.65, 132.11, 130.28, 129.41, 129.21, 121.78, 118.70, 117.86, 114.65, 112.98, 102.48, 100.33, 99.38, 94.26, 68.27, 59.34, 55.42, 51.48, 50.22, 41 .82. HRMS(ESI)C 25 H 26 N 3 O 3 + [M+H] + Calculated: 416.1969, Found: 416.1971. HPLC: 98.09% (λ=254nm, tR =11.75min).
实施例64：化合物(E)-7-((4-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丁-2-烯-1-基)氧基)-3,4-二氢喹啉-2(1H)-酮(I-C6)的制备
Example 64: Compound (E)-7-((4-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)butan-2 Preparation of -en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (I-C6)
将LRQ-05-03(99mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，(E)-7-(4-溴代丁-2-烯-1-基)氧基)-3,4-二氢喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(72mg，收率35％)。1H NMR(800MHz,CDCl3)δ8.19(s,1H),7.08(t,J＝7.9Hz,1H),7.05(d,J＝8.3Hz,1H),6.90(d,J＝8.1Hz,1H),6.57–6.50(m,2H),6.36(d,J＝2.3Hz,1H),6.28(s,1H),5.98–5.90(m,2H),4.53(d,J＝4.5Hz,2H),4.06(t,J＝5.6Hz,2H),3.94(s,3H),3.81(s,2H),3.25(d,J＝5.3Hz,2H),2.98(t,J＝5.6Hz,2H),2.90(t,J＝7.5Hz,2H),2.65–2.58(m,2H).13C NMR(201MHz,CDCl3)δ171.85,158.22,153.05,138.32,137.58,132.70,130.64,128.96,128.83,121.55,118.75,116.24,109.05,102.65,102.35,100.16,94.02,68.30,59.50,55.48,51.54,50.38,42.12,31.19,24.73.HRMS(ESI)C25H28N3O3 +[M+H]+计算值：418.2125，实测值：418.2122。HPLC:98.74％(λ＝254nm,tR＝11.84min)。After LRQ-05-03 (99mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), (E)-7-(4-bromobut-2-en-1-yl )oxy)-3,4-dihydroquinolin-2(1H)-one (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (72 mg, yield 35%). 1 H NMR (800MHz, CDCl 3 ) δ8.19(s, 1H), 7.08(t, J=7.9Hz, 1H), 7.05(d, J=8.3Hz, 1H), 6.90(d, J=8.1Hz ,1H),6.57–6.50(m,2H),6.36(d,J＝2.3Hz,1H),6.28(s,1H),5.98–5.90(m,2H),4.53(d,J＝4.5Hz, 2H), 4.06(t, J=5.6Hz, 2H), 3.94(s, 3H), 3.81(s, 2H), 3.25(d, J=5.3Hz, 2H), 2.98(t, J=5.6Hz, 2H), 2.90(t, J=7.5Hz, 2H), 2.65–2.58(m, 2H). 13 C NMR (201MHz, CDCl 3 ) δ171.85, 158.22, 153.05, 138.32, 137.58, 132.70, 130.64, 128.96, 128.83 , 121.55,118.75,116.24,109.05,102.65,102.35,100.16,94.02,68.30,59.50,55.48,51.54,50.38,42.12,31.19,24.73. O 3 + [ M +H ] + Calculated: 418.2125, Measured: 418.2122. HPLC: 98.74% (λ=254nm, tR =11.84min).
实施例65：化合物3-(反式-4-(2-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-C7)的制备
Example 65: Compound 3-(trans-4-(2-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)ethyl) )cyclohexyl)-1,1-dimethylurea (I-C7) preparation
将LRQ-05-03(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(11mg，收率23％)。1H NMR(800MHz,CDCl3)δ7.07(t,J＝7.9 Hz,1H),6.93–6.85(m,1H),6.55–6.48(m,1H),6.29(s,1H),4.06(t,J＝5.6Hz,2H),3.94(s,3H),3.80(s,2H),3.61–3.54(m,1H),2.95(t,J＝5.6Hz,2H),2.87(s,6H),2.60–2.50(m,2H),2.06–1.97(m,2H),1.81–1.76(m,2H),1.53–1.47(m,2H),1.35–1.27(m,1H),1.14–1.00(m,4H).13C NMR(201MHz,CDCl3)δ157.98,153.06,137.58,132.49,121.46,118.79,102.35,100.18,93.88,55.69,55.50,51.66,50.71,49.98,42.10,36.28(2C),35.35,34.22,34.13(2C),32.20(2C).HRMS(ESI)C23H35N4O2 +[M+H]+计算值：399.2755，实测值：399.2749。HPLC:96.99％(λ＝254nm,tR＝11.84min)。After dissolving LRQ-05-03 (24mg, 0.12mmol) in DMF (8mL), DIPEA (45mg, 0.35mmol) and LRQ-04-152 (47mg, 0.17mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (11 mg, yield 23%). 1 H NMR (800MHz, CDCl 3 ) δ7.07(t, J=7.9 Hz,1H),6.93–6.85(m,1H),6.55–6.48(m,1H),6.29(s,1H),4.06(t,J＝5.6Hz,2H),3.94(s,3H),3.80 (s,2H),3.61–3.54(m,1H),2.95(t,J＝5.6Hz,2H),2.87(s,6H),2.60–2.50(m,2H),2.06–1.97(m,2H ),1.81–1.76(m,2H),1.53–1.47(m,2H),1.35–1.27(m,1H),1.14–1.00(m,4H). 13 C NMR(201MHz,CDCl 3 )δ157.98,153.06 ,137.58,132.49,121.46,118.79,102.35,100.18,93.88,55.69,55.50,51.66,50.71,49.98,42.10,36.28(2C),35.35,34.22,34.13(2C),32.2 0(2C).HRMS(ESI) Calcd. for C23H35N4O2 + [M+H] + : 399.2755 , found: 399.2749 . HPLC: 96.99% (λ=254nm, tR =11.84min).
实施例66：化合物N-(2-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)乙基)四氢-2H-吡喃-4-甲酰胺(I-C8)的制备
Example 66: The compound N-(2-(9-methoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)ethyl)tetrahydro-2H- Preparation of pyran-4-carboxamide (I-C8)
步骤1：将LRQ-05-03(920mg,4.55mmol)和DIPEA(3.53g,27.30mmol)溶于DMF(10mL)后，加入N-Boc-2-溴乙基胺(561mg,2.51mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体(800mg，收率51％)。1H NMR(800MHz,CDCl3)δ7.09(t,J＝7.9Hz,1H),6.91(d,J＝8.1Hz,1H),6.54(d,J＝7.7Hz,1H),6.32(s,1H),4.14–4.04(m,2H),3.94(s,3H),3.86(s,2H),3.43–3.26(m,2H),3.14–2.91(m,2H),2.80–2.63(m,2H),1.43(s,9H).HRMS(ESI)C19H28N3O3 +[M+H]+计算值：346.2125，实测值：346.2131。Step 1: After dissolving LRQ-05-03 (920mg, 4.55mmol) and DIPEA (3.53g, 27.30mmol) in DMF (10mL), add N-Boc-2-bromoethylamine (561mg, 2.51mmol), React overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:1), a yellow solid (800 mg, yield 51%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.09(t, J=7.9Hz, 1H), 6.91(d, J=8.1Hz, 1H), 6.54(d, J=7.7Hz, 1H), 6.32(s ,1H),4.14–4.04(m,2H),3.94(s,3H),3.86(s,2H),3.43–3.26(m,2H),3.14–2.91(m,2H),2.80–2.63(m ,2H) , 1.43(s, 9H ). HRMS ( ESI) calcd for C19H28N3O3 + [M+H] + : 346.2125, found: 346.2131.
步骤2：将LRQ-05-113(70mg,0.20mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(155mg,1.20mmol)和四氢-2H-吡喃-4-羰基氯(44mg,0.30mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体(43mg，收率36％)。1H NMR(800MHz,CDCl3)δ7.10(t,J＝7.9Hz,1H),6.91(d,J＝8.1Hz,1H),6.55(d,J＝7.7Hz,1H),6.31(s,1H),6.18–6.07(m,1H),4.07(t,J＝5.5Hz,2H),4.00–3.95(m,2H),3.94(s,3H),3.83(s,2H),3.49–3.42(m,2H),3.40–3.32(m,2H),3.00(t,J＝5.5Hz,2H),2.72(t,J＝5.8Hz,2H),2.34–2.27(m,1H),1.82–1.74(m,2H),1.72–1.66(m,2H).13C NMR(201MHz,CDCl3)δ174.56,153.12,137.54,132.26,121.87,118.68,102.33,100.32,94.20,67.36(2C),55.94,55.50,51.38,50.35,42.24,42.17,36.11,29.38(2C).HRMS(ESI)C20H28N3O3 +[M+H]+计算值：358.2125，实测值：358.2123。HPLC:97.41％(λ＝254nm,tR＝11.75min)。Step 2: Dissolve LRQ-05-113 (70mg, 0.20mmol) in DCM (10mL), cool down to 0°C, add trifluoroacetic acid (1mL) and react for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a yellow solid (43 mg, yield 36%). 1 H NMR (800MHz, CDCl 3 ) δ7.10(t, J=7.9Hz, 1H), 6.91(d, J=8.1Hz, 1H), 6.55(d, J=7.7Hz, 1H), 6.31(s ,1H),6.18–6.07(m,1H),4.07(t,J＝5.5Hz,2H),4.00–3.95(m,2H),3.94(s,3H),3.83(s,2H),3.49– 3.42(m,2H),3.40–3.32(m,2H),3.00(t,J=5.5Hz,2H),2.72(t,J=5.8Hz,2H),2.34–2.27(m,1H),1.82 –1.74(m,2H),1.72–1.66(m,2H). 13 C NMR(201MHz,CDCl 3 )δ174.56,153.12,137.54,132.26,121.87,118.68,102.33,100.32,94.20,67.36(2C),55. 94 , 55.50, 51.38, 50.35, 42.24, 42.17, 36.11, 29.38 (2C). HRMS (ESI) Calculated for C 20 H 28 N 3 O 3 + [M+H] + : 358.2125, Found: 358.2123. HPLC: 97.41% (λ=254nm, tR =11.75min).
实施例67：化合物4,4-二氟-N-(2-(9-甲氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)乙基)环己烷-1-甲酰胺(I-C9)的制备
Example 67: Compound 4,4-Difluoro-N-(2-(9-methoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)B base) preparation of cyclohexane-1-carboxamide (I-C9)
将LRQ-05-116(70mg,0.20mmol)溶于DCM(10mL)后降温至0℃，加入三氟乙酸(1mL)后反应2小时。反应完毕后减压蒸除溶剂，得到无色油状液体后将其溶于二氯甲烷(10mL)，加入DIPEA(155mg,1.20mmol)和4,4-二氟环己烷甲酰氯(68mg,0.30mmol)，室温下反应过夜。反应完毕后加饱和碳酸氢钠水溶液(10mL)稀释，二氯甲烷(20mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:1)，得到黄色固体(91mg，收率73％)。1H NMR(800MHz,CDCl3)δ7.12–7.08(m,1H),6.94–6.88(m,1H),6.55(d,J＝7.7Hz,1H),6.32(s,1H),6.13–6.06(m,1H),4.07(t,J＝5.6Hz,2H),3.95(s,3H),3.83(s,2H),3.48–3.42(m,2H),3.00(t,J＝5.5Hz,2H),2.71(t,J＝5.8Hz,2H),2.19–2.08(m,3H),1.92–1.86(m,2H),1.84–1.78(m,2H),1.74–1.65(m,2H).13C NMR(201MHz,CDCl3)δ174.30,153.13,137.54,132.28,121.91,121.55(t,J＝549.9Hz),118.67,102.34,100.34,94.19,55.93,55.51,51.39,50.38,42.85,42.21,36.13,32.95(t,J＝25.2Hz)(2C),26.05,26.01.HRMS(ESI)C21H28F2N3O2 +[M+H]+计算值：392.2144，实测值：392.2138。HPLC:96.36％(λ＝254nm,tR＝11.90min)。LRQ-05-116 (70mg, 0.20mmol) was dissolved in DCM (10mL), cooled to 0°C, added trifluoroacetic acid (1mL) and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), and DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol), react overnight at room temperature. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:1) to obtain a yellow solid (91 mg, yield 73%). 1 H NMR (800MHz, CDCl 3 )δ7.12–7.08(m,1H),6.94–6.88(m,1H),6.55(d,J＝7.7Hz,1H),6.32(s,1H),6.13– 6.06(m,1H),4.07(t,J=5.6Hz,2H),3.95(s,3H),3.83(s,2H),3.48–3.42(m,2H),3.00(t,J=5.5Hz ,2H),2.71(t,J＝5.8Hz,2H),2.19–2.08(m,3H),1.92–1.86(m,2H),1.84–1.78(m,2H),1.74–1.65(m,2H ). 13 C NMR (201MHz, CDCl 3 ) δ174.30, 153.13, 137.54, 132.28, 121.91, 121.55 (t, J=549.9Hz), 118.67, 102.34, 100.34, 94.19, 55.93, 55.51, 51.39, 5 0.38, 42.85, 42.21 ,36.13,32.95(t,J＝25.2Hz)(2C),26.05,26.01.HRMS(ESI)C 21 H 28 F 2 N 3 O 2 + [M+H] + calculated value: 392.2144, found value: 392.2138 . HPLC: 96.36% (λ=254nm, tR =11.90min).
实施例68：化合物7-(4-(9-乙氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)丁氧基)喹啉-2(1H)-酮(I-C10)的制备
Example 68: Compound 7-(4-(9-ethoxy-3,4-dihydropyrazine[1,2-a]indol-2(1H)-yl)butoxy)quinoline-2 Preparation of (1H)-ketone (I-C10)
步骤1：将4-甲氧基吲哚-2-羧酸(5.0g,26.15mmol)溶于二氯甲烷(50mL)，氮气置换三次后将反应液降温至-78℃，加入BBr3(39.2mL,2.0M二氯甲烷溶液)。然后将反应液升温至室温反应6小时。反应完毕后降温至-30℃加甲醇(5mL)淬灭反应，随后室温搅拌1小时，加水(30mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到红棕色油状液体并将其溶解在乙醇(50mL)中，加入硫酸(0.5mL)，回流反应过夜。反应完毕后，减压蒸除溶剂，加饱和碳酸氢钠水溶液(30mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂得到红棕色油状液体LRQ-05-122，无需纯化直接投入下一步反应。HRMS(ESI)C11H12NO3 +[M+H]+计算值：206.0812，实测值：206.0814。 Step 1: Dissolve 4-methoxyindole-2-carboxylic acid (5.0g, 26.15mmol) in dichloromethane (50mL), replace with nitrogen three times and cool the reaction solution to -78°C, add BBr 3 (39.2 mL, 2.0M dichloromethane solution). Then the reaction solution was warmed up to room temperature and reacted for 6 hours. After completion of the reaction, cool down to -30°C and add methanol (5 mL) to quench the reaction, then stir at room temperature for 1 hour, add water (30 mL) to dilute, extract with ethyl acetate (50 mL*3), wash with saturated brine, and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a reddish-brown oily liquid which was dissolved in ethanol (50 mL), added sulfuric acid (0.5 mL), and refluxed overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (30 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a reddish-brown Oily liquid LRQ-05-122, directly put into the next reaction without purification. HRMS (ESI) calcd for C11H12NO3 + [M+H] + : 206.0812 , found : 206.0814.
步骤2：将LRQ-05-122和K2CO3(3.6g,26.15mmol)溶于DMF(50mL)后，加入碘乙烷(4.49g,28.76mmol)，室温搅拌反应过夜。反应完毕后加水(20mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到橙红色油状液体LRQ-05-123，无需纯化直接投入下一步反应。HRMS(ESI)C13H16NO3 +[M+H]+计算值：234.1125，实测值：234.1121。Step 2: After LRQ-05-122 and K 2 CO 3 (3.6g, 26.15mmol) were dissolved in DMF (50mL), ethyl iodide (4.49g, 28.76mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain an orange-red oily liquid LRQ-05-123, which was directly purified without purification. into the next reaction. HRMS (ESI) calcd for C13H16NO3 + [M+H] + : 234.1125 , found : 234.1121.
步骤3：将LRQ-05-123，叔丁醇钾(6.27g,52.30mmol)溶于DMF(50mL)，室温反应40分钟后，加入溴乙腈(4.40g,39.23mmol)，随后升温至60℃反应30分钟。然后将反应液降温至室温反应过夜。反应完毕后加水(30mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1:10)，得到黄色固体LRQ-05-124(0.96g，三步反应收率13％)。1H NMR(800MHz,CDCl3)δ7.53(s,1H),7.35(t,J＝8.1Hz,1H),7.01–6.97(m,1H),6.59(d,J＝7.8Hz,1H),5.58(s,2H),4.40(q,J＝7.1Hz,2H),4.19(q,J＝7.0Hz,2H),1.50(t,J＝7.0Hz,3H),1.42(t,J＝7.1Hz,3H).HRMS(ESI)C15H17N2O3 +[M+H]+计算值：273.1234，实测值：273.1231。Step 3: Dissolve LRQ-05-123, potassium tert-butoxide (6.27g, 52.30mmol) in DMF (50mL), react at room temperature for 40 minutes, add bromoacetonitrile (4.40g, 39.23mmol), then heat up to 60°C React for 30 minutes. Then the reaction solution was cooled to room temperature and reacted overnight. After the reaction was completed, it was diluted with water (30 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/ Petroleum ether=1:10) to obtain LRQ-05-124 (0.96 g, three-step reaction yield 13%) as a yellow solid. 1 H NMR (800MHz, CDCl 3 ) δ7.53(s, 1H), 7.35(t, J=8.1Hz, 1H), 7.01–6.97(m, 1H), 6.59(d, J=7.8Hz, 1H) ,5.58(s,2H),4.40(q,J=7.1Hz,2H),4.19(q,J=7.0Hz,2H),1.50(t,J=7.0Hz,3H),1.42(t,J= 7.1 Hz , 3H). HRMS (ESI) calcd for C15H17N2O3 + [ M + H] + : 273.1234, found: 273.1231.
步骤4：将LRQ-05-124(0.96g,3.53mmol)溶于四氢呋喃(10mL)后，加入四氢铝锂(536mg,14.1mmol)，回流反应4小时。反应完毕后降温至0℃加饱和氯化铵水溶液(5mL)淬灭反应，随后室温搅拌1小时，加水(30mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到橙黄色固体LRQ-05-145，无需纯化直接投入下一步反应。HRMS(ESI)C13H17N2O+[M+H]+计算值：217.1335，实测值：217.1329。Step 4: After dissolving LRQ-05-124 (0.96g, 3.53mmol) in tetrahydrofuran (10mL), add lithium aluminum hydride (536mg, 14.1mmol), and react under reflux for 4 hours. After completion of the reaction, cool down to 0°C and add saturated ammonium chloride aqueous solution (5mL) to quench the reaction, then stir at room temperature for 1 hour, add water (30mL) to dilute, extract with ethyl acetate (50mL*3), wash with saturated brine, anhydrous sodium sulfate After drying, the solvent was distilled off under reduced pressure to obtain an orange-yellow solid LRQ-05-145, which was directly put into the next reaction without purification. HRMS (ESI) calcd for C13H17N2O + [M+H] + : 217.1335 , found : 217.1329.
步骤5：将LRQ-05-145(15mg，0.07mmol)溶于DMF(8mL)后，依次加入DIPEA(54mg，0.42mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(31mg，0.11mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到橙黄色固体(14mg，收率47％)。1H NMR(800MHz,CDCl3)δ7.73–7.68(m,1H),7.42(d,J＝8.6Hz,1H),7.05(t,J＝7.9Hz,1H),6.88(d,J＝8.1Hz,1H),6.83(s,1H),6.80–6.77(m,1H),6.55–6.48(m,2H),6.34–6.31(m,1H),4.17(q,J＝7.0Hz,2H),4.12–4.04(m,4H),3.88(s,2H),3.08–2.98(m,2H),2.72–2.62(m,2H),1.94–1.87(m,2H),1.85–1.78(m,2H),1.47(t,J＝7.0Hz,3H).HRMS(ESI)C26H30N3O3 +[M+H]+计算值：432.2282，实测值：432.2284。HPLC:97.54％(λ＝254nm,tR＝11.84min)。Step 5: After dissolving LRQ-05-145 (15mg, 0.07mmol) in DMF (8mL), add DIPEA (54mg, 0.42mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (31mg, 0.11mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10), an orange-yellow solid (14 mg, yield 47%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ7.73–7.68(m, 1H), 7.42(d, J=8.6Hz, 1H), 7.05(t, J=7.9Hz, 1H), 6.88(d, J= 8.1Hz, 1H), 6.83(s, 1H), 6.80–6.77(m, 1H), 6.55–6.48(m, 2H), 6.34–6.31(m, 1H), 4.17(q, J＝7.0Hz, 2H ),4.12–4.04(m,4H),3.88(s,2H),3.08–2.98(m,2H),2.72–2.62(m,2H),1.94–1.87(m,2H),1.85–1.78(m , 2H) , 1.47 (t, J = 7.0 Hz, 3H). HRMS ( ESI) Calcd. for C26H30N3O3 + [M+H] + : 432.2282, found: 432.2284 . HPLC: 97.54% (λ=254nm, tR =11.84min).
实施例69：化合物3-(反式-4-(2-(9-乙氧基-3,4-二氢吡嗪[1,2-a]吲哚-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-C11)的制备
Example 69: Compound 3-(trans-4-(2-(9-ethoxy-3,4-dihydropyrazin[1,2-a]indol-2(1H)-yl)ethyl) ) cyclohexyl) -1, the preparation of 1-dimethylurea (I-C11)
步骤1：将LRQ-05-145(25mg，0.11mmol)溶于DMF(8mL)后，依次加入DIPEA(85mg，0.66mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(17mg，收率36％)。1H NMR(800MHz,CDCl3)δ7.04(t,J＝7.9Hz,1H),6.88(d,J＝8.1Hz,1H),6.52(d,J＝7.7Hz,1H),6.31(s,1H),4.17(q,J＝7.0Hz,2H),4.08–4.01(m,2H),3.80(s,2H),3.62–3.54(m,1H),2.98–2.92(m,2H),2.87(s,6H),2.60–2.54(m,2H),2.03–2.00(m,2H),1.83–1.75(m,2H),1.52–1.48(m,2H),1.46(t,J＝7.0Hz,3H),1.31–1.29(m,1H),1.10–1.06(m,4H).HRMS(ESI)C24H37N4O2 +[M+H]+计算值：413.2911，实测值：413.2907。HPLC:97.84％(λ＝254nm,tR＝11.82min)。Step 1: After dissolving LRQ-05-145 (25mg, 0.11mmol) in DMF (8mL), add DIPEA (85mg, 0.66mmol) and LRQ-04-152 (47mg, 0.17mmol) sequentially, and react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (17 mg, yield 36%). 1 H NMR (800MHz, CDCl 3 ) δ7.04(t, J=7.9Hz, 1H), 6.88(d, J=8.1Hz, 1H), 6.52(d, J=7.7Hz, 1H), 6.31(s ,1H),4.17(q,J＝7.0Hz,2H),4.08–4.01(m,2H),3.80(s,2H),3.62–3.54(m,1H),2.98–2.92(m,2H), 2.87(s,6H),2.60–2.54(m,2H),2.03–2.00(m,2H),1.83–1.75(m,2H),1.52–1.48(m,2H),1.46(t,J＝7.0 Hz,3H),1.31–1.29(m,1H),1.10–1.06(m,4H).HRMS(ESI)C 24 H 37 N 4 O 2 + [M+H] + calculated value: 413.2911, measured value: 413.2907. HPLC: 97.84% (λ=254nm, tR =11.82min).
实施例70：化合物1-((9-甲氧基-3,4-二氢吡嗪并[1,2-a]吲哚-2(1H)-基)甲基)环己烷-1-醇(I-C12)(IHCH-5231)的制备
Example 70: Compound 1-((9-methoxy-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)methyl)cyclohexane-1- Preparation of alcohol (I-C12) (IHCH-5231)
将LRQ-05-03(50mg,0.25mmol)溶于无水乙醇(10mL)，加入亚甲基环己烷氧化物(138mg,1.25mmol)后，升温至60℃反应过夜。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(29mg，收率37％)。1H NMR(800MHz,CDCl3)δ7.09(t,J＝7.9Hz,1H),6.91(d,J＝8.1Hz,1H),6.54(d,J＝7.7Hz,1H),6.30(s,1H),4.07(t,J＝5.5Hz,2H),4.01(s,2H),3.94(s,3H),3.23–3.12(m,2H),2.54(s,2H),1.70–1.63(m,2H),1.62–1.53(m,3H),1.50–1.45(m,2H),1.42–1.34(m,2H),1.32–1.24(m,1H).13C NMR(201MHz,CDCl3)δ153.09,137.61,132.35,121.74,118.59,102.34,100.26,98.41,70.90,66.39,55.50,53.93,53.08,41.93,36.51(2C),25.98,22.20(2C).HRMS(ESI)C19H27N2O2 +[M+H]+计算值：315.2067，实测值：315.2068。HPLC:98.92％(λ＝254nm,tR＝11.45min)。LRQ-05-03 (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), methylenecyclohexane oxide (138 mg, 1.25 mmol) was added, and the temperature was raised to 60° C. to react overnight. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain a yellow solid (29 mg, yield 37%). 1 H NMR (800MHz, CDCl 3 ) δ7.09(t, J=7.9Hz, 1H), 6.91(d, J=8.1Hz, 1H), 6.54(d, J=7.7Hz, 1H), 6.30(s ,1H),4.07(t,J＝5.5Hz,2H),4.01(s,2H),3.94(s,3H),3.23–3.12(m,2H),2.54(s,2H),1.70–1.63( m,2H), 1.62–1.53(m,3H), 1.50–1.45(m,2H), 1.42–1.34(m,2H), 1.32–1.24(m,1H). 13 C NMR (201MHz, CDCl 3 ) δ153.09,137.61,132.35,121.74,118.59,102.34,100.26,98.41,70.90,66.39,55.50,53.93,53.08,41.93,36.51(2C),25.98,22.20(2C).HRMS( ESI) C 19 H 27 N 2 O 2 + [M+H] + calcd: 315.2067, found: 315.2068. HPLC: 98.92% (λ=254nm, tR =11.45min).
实施例71：化合物7-(4-(9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)丁氧基)喹啉-2(1H)-酮(I-D1)的制备
Example 71: Compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)butyl Preparation of oxy)quinolin-2(1H)-one (I-D1)
步骤1、2、3、4、5、6：LRQ-05-36以2-硝基-3-氟苯甲醚为原料，合成方法与文献European Journal of Medicinal Chemistry 186(2020)111881相同，LRQ-05-03为红棕色固体(六步反应收率20％)。1H NMR(800MHz,CDCl3)δ7.17(t,J＝7.9Hz,1H),6.92(d,J＝8.0Hz,1H),6.70(d,J＝7.9Hz,1H),4.38–4.25(m,2H),4.16–4.05(m,2H),3.99(s,3H),3.49–3.33(m,2H).13C NMR(201MHz,CDCl3)δ151.28,147.47,135.85,132.46,123.14,103.49,101.93,55.87,44.81,43.04,42.72.HRMS(ESI)C11H14N3O+[M+H]+计算值：204.1131,实测值：204.1134。Steps 1, 2, 3, 4, 5, 6: LRQ-05-36 uses 2-nitro-3-fluoroanisole as a raw material, and the synthesis method is the same as the document European Journal of Medicinal Chemistry 186(2020) 111881, LRQ -05-03 is a reddish-brown solid (6-step reaction yield 20%). 1 H NMR (800MHz, CDCl 3 ) δ7.17(t, J=7.9Hz, 1H), 6.92(d, J=8.0Hz, 1H), 6.70(d, J=7.9Hz, 1H), 4.38–4.25 (m,2H),4.16–4.05(m,2H),3.99(s,3H),3.49–3.33(m,2H). 13 C NMR(201MHz,CDCl 3 )δ151.28,147.47,135.85,132.46,123.14, 103.49, 101.93, 55.87, 44.81, 43.04, 42.72. HRMS (ESI) Calculated for C 11 H 14 N 3 O + [M+H] + : 204.1131, Found: 204.1134.
步骤7：将LRQ-05-36(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(119mg，收率58％)。1H NMR(800MHz,CDCl3)δ12.07(s,1H),7.69(d,J＝9.4Hz,1H),7.41(d,J＝8.7Hz,1H),7.15(t,J＝8.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.85(s,1H),6.81–6.77(m,1H),6.69(d,J＝7.9Hz,1H),6.54–6.48(m,1H),4.12–4.07(m,4H),4.00(s,3H),3.93(s,2H),3.03(t,J＝5.5Hz,2H),2.69(t,J＝7.1Hz,2H),1.93–1.86(m,2H),1.83–1.76(m,2H).13C NMR(201MHz,CDCl3)δ164.91,161.43,151.24,148.08,140.96,140.44,135.59,132.83,129.16,122.96,118.01,114.31,112.71,103.26,101.95,99.14,68.05,57.15,55.84,52.07,49.78,42.22,26.95,23.62.HRMS(ESI)C24H27N4O3 +[M+H]+计算值：419.2078，实测值：419.2072。HPLC:95.92％(λ＝254nm,tR＝12.47min)。Step 7: After dissolving LRQ-05-36 (100mg, 0.49mmol) in DMF (8mL), add DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)quinoline-2(1H) in sequence - Ketone (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (119 mg, yield 58%). 1 H NMR (800MHz, CDCl 3 ) δ12.07(s, 1H), 7.69(d, J=9.4Hz, 1H), 7.41(d, J=8.7Hz, 1H), 7.15(t, J=8.0Hz ,1H),6.91(d,J=8.0Hz,1H),6.85(s,1H),6.81–6.77(m,1H),6.69(d,J=7.9Hz,1H),6.54–6.48(m, 1H), 4.12–4.07(m, 4H), 4.00(s, 3H), 3.93(s, 2H), 3.03(t, J＝5.5Hz, 2H), 2.69(t, J＝7.1Hz, 2H), 1.93–1.86(m,2H),1.83–1.76(m,2H). 13 C NMR(201MHz,CDCl 3 )δ164.91,161.43,151.24,148.08,140.96,140.44,135.59,132.83,129.16,122.96, 118.01, 114.31 ,112.71,103.26,101.95,99.14,68.05,57.15,55.84,52.07,49.78,42.22,26.95,23.62.HRMS(ESI)C 24 H 27 N 4 O 3 + [M+H] + calculated value: 419.2078, measured Value: 419.2072. HPLC: 95.92% (λ=254nm, tR =12.47min).
实施例72：化合物7-(4-(9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(I-D2)的制备
Example 72: Compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)butyl Preparation of oxy)-3,4-dihydroquinolin-2(1H)-one (I-D2)
将LRQ-05-36(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(4-溴丁氧基)-3,4-二氢喹啉-2(1H)-酮(220mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(58mg，收率28％)。1H NMR(800MHz,CDCl3)δ8.23(s,1H),7.17(t,J＝8.0Hz,1H),7.01(d,J＝8.3Hz,1H),6.92(d,J＝8.0Hz,1H),6.70(d,J＝7.9Hz,1H),6.53–6.46(m,1H),6.34(d,J＝2.0Hz,1H),4.09(t,J＝5.5Hz,2H),4.00(s,3H),3.98–3.93(m,4H),3.03(t,J＝5.5Hz,2H),2.86(t,J＝7.5Hz,2H),2.68(t,J＝7.1Hz,2H),2.61–2.57(m,2H),1.87–1.82(m,2H),1.80–1.74(m,2H).13C NMR(201MHz,CDCl3)δ171.83,158.68,151.18,148.00,138.29,135.48,132.87,128.74,123.12,115.91,108.67,103.41,102.41,101.94,67.79,57.13,55.87,51.88,49.76,42.19,31.21,27.02,24.70,23.60.HRMS(ESI)C24H29N4O3 +[M+H]+计算值：421.2234，实测值：421.2239。HPLC:96.98％(λ＝254nm,tR＝12.33min)。After LRQ-05-36 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(4-bromobutoxy)-3,4-dihydroquinoline- 2(1H)-Kone (220mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (58 mg, yield 28%). 1 H NMR (800MHz, CDCl 3 ) δ8.23(s, 1H), 7.17(t, J=8.0Hz, 1H), 7.01(d, J=8.3Hz, 1H), 6.92(d, J=8.0Hz ,1H),6.70(d,J=7.9Hz,1H),6.53–6.46(m,1H),6.34(d,J=2.0Hz,1H),4.09(t,J=5.5Hz,2H),4.00 (s,3H),3.98–3.93(m,4H),3.03(t,J=5.5Hz,2H),2.86(t,J=7.5Hz,2H),2.68(t,J=7.1Hz,2H) ,2.61–2.57(m,2H),1.87–1.82(m,2H),1.80–1.74(m,2H). 13 C NMR(201MHz,CDCl 3 )δ171.83,158.68,151.18,148.00,138.29,135.48,132.87 24 H 29 N 4 O 3 + [M +H] + Calculated: 421.2234, Found: 421.2239. HPLC: 96.98% (λ=254nm, tR =12.33min).
实施例73：化合物7-(3-(9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)丙氧基)喹啉-2(1H)-酮(I-D3)的制备
Example 73: Compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)propane Preparation of oxy)quinolin-2(1H)-one (I-D3)
将LRQ-05-36(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)喹啉-2(1H)-酮(208mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(61mg，收率31％)。1H NMR(800MHz,CDCl3)δ12.19(s,1H),7.71–7.67(m,1H),7.42(d,J＝8.7Hz,1H),7.15(t,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,1H),6.86(d,J＝1.8Hz,1H),6.82–6.78(m,1H),6.69(d,J＝7.9Hz,1H),6.51(d,J＝9.3Hz,1H),4.15(t,J＝6.0Hz,2H),4.11(t,J＝5.5Hz,2H),4.00(s,3H),3.96(s,2H),3.06(t,J＝5.5Hz,2H),2.82(t,J＝7.0Hz,2H),2.12–2.07(m,2H).13C NMR(201MHz,CDCl3)δ164.95,161.31,151.25,147.94,140.92,140.45,135.58,132.39,129.17,123.02,118.12,114.39,112.54,103.30,101.97,99.30,66.14,55.85,54.09,52.06,49.96,42.21,26.94.HRMS(ESI)C23H25N4O3 +[M+H]+计算值：405.1921，实测值：405.1918。HPLC:96.89％(λ＝254nm,tR＝11.48min)。 After LRQ-05-36 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one ( 208mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (61 mg, yield 31%). 1 H NMR (800MHz, CDCl 3 ) δ12.19(s, 1H), 7.71–7.67(m, 1H), 7.42(d, J=8.7Hz, 1H), 7.15(t, J=8.0Hz, 1H) ,6.92(d,J=8.0Hz,1H),6.86(d,J=1.8Hz,1H),6.82–6.78(m,1H),6.69(d,J=7.9Hz,1H),6.51(d, J＝9.3Hz, 1H), 4.15(t, J＝6.0Hz, 2H), 4.11(t, J＝5.5Hz, 2H), 4.00(s, 3H), 3.96(s, 2H), 3.06(t, J＝5.5Hz, 2H), 2.82(t, J＝7.0Hz, 2H), 2.12–2.07(m, 2H). 13 C NMR (201MHz, CDCl 3 ) δ164.95, 161.31, 151.25, 147.94, 140.92, 140.45, 23 H 25 N 4 O 3 + [M+ H] + Calculated: 405.1921, Found: 405.1918. HPLC: 96.89% (λ=254nm, tR =11.48min).
实施例74：化合物7-(3-(9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-D4)的制备
Example 74: Compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)propane Preparation of oxy)-3,4-dihydroquinolin-2(1H)-one (I-D4)
将LRQ-05-36(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，7-(3-溴丙氧基)-3,4-二氢喹啉-2(1H)-酮(209mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(74mg，收率37％)。1H NMR(800MHz,CDCl3)δ7.16(t,J＝7.9Hz,1H),7.02(d,J＝8.2Hz,1H),6.95–6.88(m,1H),6.69(d,J＝7.9Hz,1H),6.55–6.48(m,1H),6.35(s,1H),4.10(t,J＝5.4Hz,2H),4.02(t,J＝6.0Hz,2H),4.00(s,3H),3.93(s,2H),3.04(t,J＝5.4Hz,2H),2.87(t,J＝7.4Hz,2H),2.79(t,J＝7.0Hz,2H),2.60(t,J＝7.5Hz,2H),2.08–2.00(m,2H).13C NMR(201MHz,CDCl3)δ171.84,158.64,151.34,147.96,138.21,135.65,133.02,128.78,122.92,115.97,108.71,103.19,102.33,101.90,65.93,55.82,54.14,52.12,50.02,42.19,31.17,27.07,24.70.HRMS(ESI)C23H27N4O3 +[M+H]+计算值：407.2078，实测值：407.2073。HPLC:98.49％(λ＝254nm,tR＝11.55min)。After LRQ-05-36 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), 7-(3-bromopropoxy)-3,4-dihydroquinoline- 2(1H)-ketone (209mg, 0.74mmol) was reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (74 mg, yield 37%). 1 H NMR (800MHz, CDCl 3 ) δ7.16(t, J=7.9Hz, 1H), 7.02(d, J=8.2Hz, 1H), 6.95–6.88(m, 1H), 6.69(d, J= 7.9Hz, 1H), 6.55–6.48(m, 1H), 6.35(s, 1H), 4.10(t, J＝5.4Hz, 2H), 4.02(t, J＝6.0Hz, 2H), 4.00(s, 3H), 3.93(s, 2H), 3.04(t, J=5.4Hz, 2H), 2.87(t, J=7.4Hz, 2H), 2.79(t, J=7.0Hz, 2H), 2.60(t, J＝7.5Hz, 2H), 2.08–2.00(m, 2H). 13 C NMR (201MHz, CDCl 3 ) δ171.84, 158.64, 151.34, 147.96, 138.21, 135.65, 133.02, 128.78, 122.92, 115.97, 108.71 ,103.19, 102.33,101.90,65.93,55.82,54.14,52.12,50.02,42.19,31.17,27.07,24.70. HRMS(ESI)C 23 H 27 N 4 O 3 + [M+H] + Calculated: 407.2078, Found: 407.2073 . HPLC: 98.49% (λ=254nm, tR =11.55min).
实施例75：化合物(E)-7-((4-(9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)丁-2-烯-1-基)氧基)-3,4-二氢喹啉-2(1H)-酮(I-D5)的制备
Example 75: Compound (E)-7-((4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H )-yl)but-2-en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (I-D5) preparation
将LRQ-05-36(100mg，0.49mmol)溶于DMF(8mL)后，依次加入DIPEA(189mg，1.47mmol)，(E)-7-(4-溴代丁-2-烯-1-基)氧基)-3,4-二氢喹啉-2(1H)-酮(218mg，0.74mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(109mg，收率53％)。1H NMR(800MHz,CDCl3)δ8.27(s,1H),7.16(t,J＝8.0Hz,1H),7.04(d,J＝8.3Hz,1H),6.92(d,J＝8.0Hz,1H),6.69(d,J＝7.9Hz,1H),6.56–6.51(m,1H),6.36(d,J＝2.4Hz,1H),5.99–5.87(m,2H),4.55–4.48(m,2H),4.09(t,J＝5.5Hz,2H),4.00(s,3H),3.92(s,2H),3.29(d,J＝5.3Hz,2H),3.02(t,J＝5.5Hz,2H),2.89(t,J＝7.5Hz,2H),2.64–2.56(m,2H).13C NMR(201MHz,CDCl3)δ171.87,158.20,151.36, 147.87,138.32,135.68,133.12,129.81,129.40,128.84,122.90,116.25,109.01,103.20,102.63,101.90,68.17,59.10,55.84,52.14,49.31,42.13,31.18,24.72.HRMS(ESI)C24H27N4O3 +[M+H]+计算值：419.2078，实测值：419.2081。HPLC:98.33％(λ＝254nm,tR＝11.81min)。After LRQ-05-36 (100mg, 0.49mmol) was dissolved in DMF (8mL), DIPEA (189mg, 1.47mmol), (E)-7-(4-bromobut-2-en-1-yl )oxy)-3,4-dihydroquinolin-2(1H)-one (218mg, 0.74mmol), react overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (109 mg, yield 53%). 1 H NMR (800MHz, CDCl 3 ) δ8.27(s, 1H), 7.16(t, J=8.0Hz, 1H), 7.04(d, J=8.3Hz, 1H), 6.92(d, J=8.0Hz ,1H),6.69(d,J=7.9Hz,1H),6.56–6.51(m,1H),6.36(d,J=2.4Hz,1H),5.99–5.87(m,2H),4.55–4.48( m,2H),4.09(t,J=5.5Hz,2H),4.00(s,3H),3.92(s,2H),3.29(d,J=5.3Hz,2H),3.02(t,J=5.5 Hz, 2H), 2.89 (t, J=7.5Hz, 2H), 2.64–2.56 (m, 2H). 13 C NMR (201MHz, CDCl 3 ) δ171.87, 158.20, 151.36, 147.87,138.32,135.68,133.12,129.81,129.40,128.84,122.90,116.25,109.01,103.20,102.63,101.90,68.17,59.10,55.84,52.14,49.31, 42.13, 31.18, 24.72. HRMS (ESI) C 24 H 27 N 4 O 3 + [M+H] + calcd: 419.2078, found: 419.2081. HPLC: 98.33% (λ=254nm, tR =11.81min).
实施例76：化合物3-(反式-4-(2-(9-甲氧基-3,4-二氢苯并[4,5]咪唑[1,2-a]吡嗪-2(1H)-基)乙基)环己基)-1,1-二甲基脲(I-D6)的制备
Example 76: Compound 3-(trans-4-(2-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H )-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-D6) preparation
将LRQ-05-36(24mg，0.12mmol)溶于DMF(8mL)后，依次加入DIPEA(45mg，0.35mmol)，LRQ-04-152(47mg，0.17mmol)，100℃反应过夜。反应完毕后加水(10mL)稀释，乙酸乙酯(50mL*3)萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到黄色固体(12mg，收率25％)。1H NMR(800MHz,CDCl3)δ7.16(t,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),6.70(d,J＝7.9Hz,1H),4.12(d,J＝7.5Hz,1H),4.10(t,J＝5.5Hz,2H),4.01(s,3H),3.89(s,2H),3.61–3.54(m,1H),3.00(t,J＝5.5Hz,2H),2.87(s,6H),2.65–2.59(m,2H),2.05–1.99(m,2H),1.81–1.77(m,2H),1.53–1.47(m,2H),1.35–1.28(m,1H),1.14–1.03(m,4H).13C NMR(201MHz,CDCl3)δ157.97,151.28,148.17,135.65,132.94,122.89,103.21,101.93,55.84,55.44,52.21,49.94,49.79,42.20,36.27(2C),35.10,34.07(2C),34.03,32.11(2C).HRMS(ESI)C22H34N5O2 +[M+H]+计算值：400.2707，实测值：400.2699。HPLC:97.29％(λ＝254nm,tR＝11.14min)。After dissolving LRQ-05-36 (24mg, 0.12mmol) in DMF (8mL), DIPEA (45mg, 0.35mmol) and LRQ-04-152 (47mg, 0.17mmol) were added sequentially, and reacted overnight at 100°C. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloro Methane=1:10) to obtain a yellow solid (12 mg, yield 25%). 1 H NMR (800MHz, CDCl 3 ) δ7.16(t, J=8.0Hz, 1H), 6.93(d, J=8.0Hz, 1H), 6.70(d, J=7.9Hz, 1H), 4.12(d ,J=7.5Hz,1H),4.10(t,J=5.5Hz,2H),4.01(s,3H),3.89(s,2H),3.61–3.54(m,1H),3.00(t,J= 5.5Hz, 2H), 2.87(s, 6H), 2.65–2.59(m, 2H), 2.05–1.99(m, 2H), 1.81–1.77(m, 2H), 1.53–1.47(m, 2H), 1.35 –1.28(m,1H),1.14–1.03(m,4H). 13 C NMR(201MHz,CDCl 3 )δ157.97,151.28,148.17,135.65,132.94,122.89,103.21,101.93,55.84,55.44,52.21,4 9.94, 49.79,42.20,36.27(2C),35.10,34.07(2C),34.03,32.11(2C).HRMS(ESI)C 22 H 34 N 5 O 2 + [M+H] + Calculated: 400.2707, Found: 400.2699. HPLC: 97.29% (λ=254nm, tR =11.14min).
实施例77：化合物1-((9-甲氧基-3,4-二氢苯并[4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)甲基)环己烷-1-醇(I-D7)(IHCH-5230)的制备
Example 77: Compound 1-((9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)methyl) Preparation of Cyclohexane-1-ol (I-D7) (IHCH-5230)
将LRQ-05-36(50mg,0.25mmol)溶于无水乙醇(10mL)，加入亚甲基环己烷氧化物(138mg,1.25mmol)后，升温至60℃反应过夜。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯化(甲醇/二氯甲烷＝1:10)，得到白色固体(10mg，收率13％)。1H NMR(800MHz,CDCl3)δ7.16(t,J＝8.0Hz,1H),6.95–6.89(m,1H),6.69(d,J＝7.9Hz,1H),4.14–4.05(m,4H),3.99(s,3H),3.25–3.16(m,2H),2.58(s,2H),1.67–1.60(m,2H),1.60–1.51(m,3H),1.49–1.43(m,2H),1.42–1.36(m,2H),1.30–1.26(m,1H).13C NMR(201MHz,CDCl3)δ151.31,148.03,135.64,132.85,123.01,103.19,101.90,71.27, 66.48,55.79,54.53,52.18,42.09,36.25(2C),25.90,22.12(2C).HRMS(ESI)C18H26N3O2 +[M+H]+计算值：316.2020，实测值：316.2025。HPLC:99.78％(λ＝254nm,tR＝11.67min)。LRQ-05-36 (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), methylenecyclohexane oxide (138 mg, 1.25 mmol) was added, and the temperature was raised to 60° C. to react overnight. After the reaction was complete, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol/dichloromethane=1:10) to obtain a white solid (10 mg, yield 13%). 1 H NMR (800MHz, CDCl 3 ) δ7.16(t, J=8.0Hz, 1H), 6.95–6.89(m, 1H), 6.69(d, J=7.9Hz, 1H), 4.14–4.05(m, 4H),3.99(s,3H),3.25–3.16(m,2H),2.58(s,2H),1.67–1.60(m,2H),1.60–1.51(m,3H),1.49–1.43(m, 2H),1.42–1.36(m,2H),1.30–1.26(m,1H). 13 C NMR(201MHz,CDCl 3 )δ151.31,148.03,135.64,132.85,123.01,103.19,101.90,71.27, 66.48,55.79,54.53,52.18,42.09,36.25(2C),25.90,22.12(2C).HRMS(ESI)C 18 H 26 N 3 O 2 + [M+H] + Calculated: 316.2020, Found: 316.2025 . HPLC: 99.78% (λ=254nm, tR =11.67min).
生物测试例1：通式(I)化合物对于多巴胺D2受体的亲和力测试Biological test example 1: Affinity test of the compound of general formula (I) for dopamine D2 receptor
本发明化合物对于多巴胺D2受体的亲和力采用放射性配体竞争性实验的方法进行测定。The affinity of the compound of the present invention for the dopamine D2 receptor is determined by the method of radioligand competition experiment.
实验步骤：Experimental steps:
第一步，制备含有特定多巴胺D2受体的细胞膜组分。10cm培养皿以10ng多巴胺D2受体和40μL PEI进行转染，48小时后，从细胞房拿出10厘米培养皿，其中培养的细胞已表达多巴胺D2受体。用真空泵吸掉培液，每孔加入3mL裂解液，将细胞置于4℃冷库，静置10分钟。待细胞脱落后，将其转移到15mL离心管中，4℃离心机1500rpm离心5分钟，弃上清。将细胞沉淀转移到组织匀浆器中，再向其中加入3mL裂解液，充分研磨至细胞破碎。然后，将细胞悬液等分至多个EP管中，4℃离心机12000rpm离心5min，弃上清。沉淀即为含有多巴胺D2受体的细胞膜组分。In the first step, cell membrane fractions containing specific dopamine D2 receptors are prepared. A 10 cm culture dish was transfected with 10 ng dopamine D 2 receptor and 40 μL PEI. After 48 hours, the 10 cm culture dish was taken out from the cell room, in which the cultured cells had expressed dopamine D 2 receptor. Use a vacuum pump to suck off the culture medium, add 3mL of lysate to each well, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing dopamine D2 receptors.
第二步，对瞬时表达多巴胺D2受体的293T膜组分进行配体受体结合实验。首先，向含有多巴胺D2受体的细胞膜组分加入标准结合缓冲液，用电动组织匀浆器将细胞膜破碎重悬。96孔板每孔加入30μL膜蛋白悬液。然后，96孔板从左到右依次加入30μL不同药物，保证药物终浓度由下到上依次为10-5M、10-6M、10-7M、10-8M、10-9M、0M，每种处理两个重复。紧接着，96孔板每孔加入30μL[3H]-Methylspiperone。室温避光孵育2小时。检测。机器读值反应膜上结合[3H]-Methylspiperone的量，进一步数据处理后得到不同化合物对多巴胺D2受体的亲和力Ki值。In the second step, ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing dopamine D2 receptors. First, standard binding buffer was added to the cell membrane fraction containing dopamine D2 receptor, and the cell membrane was broken and resuspended with an electric tissue homogenizer. Add 30 μL of membrane protein suspension to each well of a 96-well plate. Then, 30 μL of different drugs were added to the 96-well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment. Immediately afterwards, 30 μL of [ 3 H]-Methylspiperone was added to each well of the 96-well plate. Incubate at room temperature for 2 hours in the dark. detection. The machine reading value reflects the amount of [ 3 H]-Methylspiperone bound on the membrane, and after further data processing, the affinity K i value of different compounds for dopamine D2 receptors is obtained.
结果如表1所示。结果表明，化合物I-A1到化合物I-D7对多巴胺D2受体均有一定的亲和活性，可见本发明的化合物对多巴胺D2受体均有一定的亲和活性。The results are shown in Table 1. The results show that compounds I-A1 to I-D7 all have a certain affinity activity for dopamine D2 receptors, and it can be seen that the compounds of the present invention all have certain affinity activities for dopamine D2 receptors.
表1Table 1
化合物compound 亲和力Ki(pKi±SEM)(nM)Affinity Ki(pKi±SEM)(nM)
I-A1I-A1 84.42(7.07±0.02)84.42(7.07±0.02)
I-A2I-A2 113.41(7.41±0.45)113.41(7.41±0.45)
I-A5I-A5 290.35(6.54±0.01)290.35(6.54±0.01)
I-A8I-A8 149.05(6.82±0.16)149.05(6.82±0.16)
I-A9I-A9 203.86(6.69±0.17)203.86(6.69±0.17)
I-A10I-A10 138.99(6.85±0.19)138.99(6.85±0.19)
I-A12I-A12 436.43(6.43±0.19)436.43(6.43±0.19)
I-A13I-A13 1721(5.80±0.12)1721(5.80±0.12)
I-A14I-A14 751.9751.9
I-A15I-A15 272.2272.2
I-A16I-A16 16.54(7.78±0.41)16.54(7.78±0.41)
I-A18I-A18 88.78(7.05±0.09)88.78(7.05±0.09)
I-A19I-A19 929.68(6.03±0.07)929.68(6.03±0.07)
I-A20I-A20 89.53(7.05±0.07)89.53(7.05±0.07)
I-A21I-A21 523.6(6.28±0.28)523.6(6.28±0.28)
I-A25I-A25 37.97(7.42±0.05)37.97(7.42±0.05)
I-A28I-A28 102.56(6.99±0.21)102.56(6.99±0.21)
I-A29I-A29 27.67(7.56±0.16)27.67(7.56±0.16)
I-A30I-A30 151.18(6.82±0.12)151.18(6.82±0.12)
I-A34I-A34 604.64(6.21±0.06)604.64(6.21±0.06)
I-A45I-A45 714.49(6.14±0.15)714.49(6.14±0.15)
I-B1I-B1 361.63(7.08±0.81)361.63(7.08±0.81)
I-B2I-B2 78.91(7.11±0.04)78.91(7.11±0.04)
I-B3I-B3 282.16(6.54±0.33)282.16(6.54±0.33)
I-B4I-B4 727.78(6.13±0.26)727.78(6.13±0.26)
I-B6I-B6 266.07(6.58±0.41)266.07(6.58±0.41)
I-B7I-B7 2.71(8.74±0.33)2.71(8.74±0.33)
I-B8I-B8 381.07(6.41±0.16)381.07(6.41±0.16)
I-B10I-B10 23.25(7.63±0.57)23.25(7.63±0.57)
I-C1I-C1 400.83(6.57±0.26)400.83(6.57±0.26)
I-C2I-C2 220.95(7.21±0.50)220.95(7.21±0.50)
I-C5I-C5 437.5(6.36±0.28)437.5(6.36±0.28)
I-C8I-C8 239.2239.2
I-D6I-D6 16.83(7.89±0.25)16.83(7.89±0.25)
备注：数据使用[3H]-Methylspiperone(0.3-0.5nM)作为放射性配体的竞争结合实验的平均Ki(pKi±SEM)。Remarks: Data are mean K i (pK i ± SEM) of competition binding experiments using [ 3 H]-Methylspiperone (0.3-0.5 nM) as radioligand.
生物测试例2：化合物对于多巴胺D2受体的功能活性测试Biological Test Example 2: Functional Activity Test of Compounds for Dopamine D2 Receptors
为了检测多巴胺D2受体介导的下游G蛋白信号通路，第一天，6厘米培养皿以1μg多巴胺D2受体、1μg含有C端海藻荧光素酶的Gαi1(Gαi1-Rluc)、1μg Gβ3、1μg含有C端绿色荧光蛋白的Gγ9(Gγ9-GFP)和16μL PEI进行转染。同时，为了检测多巴胺D2受体介导的下游β-arrestin2信号通路，第一天，6厘米培养皿以500μg含有C端海藻荧光素酶的多巴胺D2受体(D2-Rluc)、500μg G蛋白偶联受体激酶2(GRK2)、2500μg含有N端绿色荧光蛋白的β-arrestin2(GFP2-ARRB2)和14μL PEI进行转染。第二天，消化长满的细胞，以一个长满细胞的6厘米培养皿细胞量铺一个96孔板，每孔 100μL培液。第三天，加药检测。从细胞房中拿出96孔板去除培液，每孔加入40μL底物腔肠素400a(终浓度5μM)，紧接着从左到右依次加入20μL不同的药物，保证药物终浓度由下到上梯度递减，每种处理两个重复，最后，上机检测。机器读值反应胞内β-arrestin2上膜情况以及G蛋白三聚体解离情况，前者表征多巴胺D2受体下游β-arrestin2信号通路激活程度后者表征多巴胺D2受体下游G蛋白信号通路激活程度，由此，各种化合物对多巴胺D2受体的激动作用可被揭示。结果如表2所示。In order to detect the downstream G protein signaling pathway mediated by dopamine D receptors, on the first day, 6 cm dishes were treated with 1 μg dopamine D receptors, 1 μg Gα i1 containing C-terminal seaweed luciferase (Gα i1 -Rluc), 1 μg G β3 , 1 μg Gγ 9 containing C-terminal green fluorescent protein (Gγ 9 -GFP) and 16 μL PEI were used for transfection. At the same time, in order to detect the downstream β-arrestin2 signaling pathway mediated by dopamine D2 receptor, on the first day, 6 cm culture dishes were treated with 500 μg dopamine D2 receptor ( D2 -Rluc) containing C-terminal seaweed luciferase, 500 μg G protein-coupled receptor kinase 2 (GRK2), 2500 μg β-arrestin2 (GFP2-ARRB2) containing N-terminal green fluorescent protein and 14 μL PEI were used for transfection. The next day, digest the overgrown cells and spread a 96-well plate with the amount of cells in a 6 cm culture dish full of cells, each well 100 μL culture medium. On the third day, dosing test. Take out the 96-well plate from the cell room to remove the culture medium, add 40 μL of the substrate coelenterazine 400a (final concentration 5 μM) to each well, and then add 20 μL of different drugs in turn from left to right to ensure that the final drug concentration is from bottom to top Gradient descending, two repetitions for each treatment, and finally, testing on the machine. The machine reading value reflects the situation on the intracellular β-arrestin2 membrane and the dissociation of the G protein trimer. The former indicates the activation degree of the β-arrestin2 signaling pathway downstream of the dopamine D 2 receptor, and the latter indicates the G protein signaling pathway downstream of the dopamine D 2 receptor. The degree of activation, and thus the agonistic effect of various compounds on the dopamine D2 receptor can be revealed. The results are shown in Table 2.
结果表明，化合物I-A1到化合物I-D7对多巴胺D2受体均有一定的激动活性。The results show that compounds I-A1 to I-D7 all have certain agonistic activity on dopamine D 2 receptors.
表2



Table 2



备注：所有数据均为三次独立测定的mean±SEM(n＝3次独立实验)。1EC50是在实验中给出半数最大反应的化合物浓度。2括号Emax％表示化合物在实验中产生的最大反应强度(Emax)相对于内源性配体多巴胺的百分比。Remarks: All data are mean±SEM of three independent determinations (n=3 independent experiments). 1 The EC50 is the concentration of compound that gives the half maximal response in the experiment. 2 Brackets E max % represent the percentage of the maximum response intensity (E max ) produced by the compound in the experiment relative to the endogenous ligand dopamine.
生物测试例3：通式(I)化合物对于5-羟色胺1A(5-HT1A)受体的亲和力测试Biological test example 3: Affinity test of the compound of general formula (I) for 5-hydroxytryptamine 1A (5-HT 1A ) receptor
本发明化合物对于5-羟色胺1A(5-HT1A)受体的亲和力采用放射性配体竞争性实验的方法进行测定。The affinity of the compound of the present invention for 5-hydroxytryptamine 1A (5-HT 1A ) receptor is determined by radioligand competition experiment method.
实验步骤：Experimental steps:
第一步，制备含有特定血清素1A受体的细胞膜组分。铺有HEK-293T细胞的10cm培养皿以10μg血清素1A受体和40μL PEI进行转染，48小时后，从培养箱中取出10cm培养皿，其中培养的细胞已表达血清素1A受体。用真空泵吸掉培养基，每皿加入3mL裂解液，将细胞置于4℃冷库，静置10分钟。待细胞脱落后，将其转移到15mL离心管中，4℃离心机1500rpm离心5分钟，弃上清。将细胞沉淀转移到组织匀浆器中，再向其中加入3mL裂解液，充分研磨至细胞破碎。然后，将细胞悬液等分至多个EP管中，4℃离心机12000rpm离心5min，弃上清。沉淀即为含有血清素1A受体的细胞膜组分。In the first step, cell membrane fractions containing specific serotonin 1A receptors are prepared. The 10cm culture dish covered with HEK-293T cells was transfected with 10μg serotonin 1A receptor and 40μL PEI. After 48 hours, the 10cm culture dish was taken out from the incubator, in which the cultured cells had expressed serotonin 1A receptor. Suck off the medium with a vacuum pump, add 3mL of lysate to each dish, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing the serotonin 1A receptor.
第二步，对瞬时表达血清素1A受体的293T膜组分进行配体受体结合实验。首先，向含有血清素1A受体的细胞膜组分中加入标准结合缓冲液，用电动组织匀浆器将细胞膜破碎重悬。96孔板每孔加入30μL膜蛋白悬液。然后，96孔板从左到右依次加入30μL不同药物，保证药物终浓度由下到上依次为10-5M、10-6M、10-7M、10-8M、10-9M、0M，每种处理两个重复。紧接着，96孔板每孔加入30μL[3H]-LSD。室温避光孵育2小时，检测。仪器读值反映膜上结合[3H]-LSD的量，进一步数据处理后得到不同化合物对血清素1A受体的结合亲和力Ki的值。In the second step, the ligand-receptor binding experiment was performed on the 293T membrane fraction transiently expressing the serotonin 1A receptor. First, add standard binding buffer to the cell membrane fraction containing the serotonin 1A receptor, and use an electric tissue homogenizer to break and resuspend the cell membrane. Add 30 μL of membrane protein suspension to each well of a 96-well plate. Then, 30 μL of different drugs were added to the 96-well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment. Immediately afterwards, 30 μL of [ 3 H]-LSD was added to each well of the 96-well plate. Incubate at room temperature in the dark for 2 hours and detect. The reading value of the instrument reflects the amount of [ 3 H]-LSD bound on the membrane, and after further data processing, the value of the binding affinity Ki of different compounds to the serotonin 1A receptor is obtained.
实验步骤：Experimental steps:
结果如表3所示。该结果表明，本发明的化合物对5-羟色胺1A(5-HT1A)受体有很强的亲和活性。The results are shown in Table 3. This result shows that the compound of the present invention has strong affinity activity on 5-hydroxytryptamine 1A (5-HT 1A ) receptor.
表3table 3
化合物compound 亲和力KiAffinity Ki
I-A15I-A15 5.43nM5.43nM
I-A22I-A22 0.073nM0.073nM
I-A27I-A27 0.64nM0.64nM
I-A32I-A32 2.55nM2.55nM
I-A41I-A41 0.78nM0.78nM
I-A42I-A42 0.42nM0.42nM
I-A43I-A43 0.015nM0.015nM
阿立哌唑Aripiprazole 53.79nM53.79nM
卡利拉嗪Cariprazine 9.94nM9.94nM
生物测试例4：化合物对于5-羟色胺1A(5-HT1A)受体的功能活性测试Biological test example 4: Functional activity test of compounds for 5-hydroxytryptamine 1A (5-HT 1A ) receptors
为检测血清素1A受体介导的下游G蛋白信号通路，第一天，铺有HEK-293T细胞的6cm培养皿以1μg血清素1A受体、1μg含有C端海藻荧光素酶的Gαi1(Gαi1-Rluc)、1μg Gβ3、1μg含有C端绿色荧光蛋白的Gγ9(Gγ9-GFP)和16μL PEI进行转染。同时，为了检测血清素1A受体介导的下游β-arrestin2信号通路，第一天，6cm培养皿以500ng含有C端海藻荧光素酶的血清素1A受体(5HT1AR-Rluc)、500ng G蛋白偶联受体激酶2(GRK2)、2500ng含有N端绿色荧光蛋白的β-arrestin2(GFP2-ARRB2)和14μL PEI进行转染。第二天，消化长满的细胞，以一个长满细胞的6cm培养皿的细胞量铺一个96孔板，每孔100μL培养基。第三天，加药检测。从细胞房中拿出96孔板去除培养基，每孔加入40μL底物腔肠素400a(终浓度5μM)，紧接着从左到右依次加入20μL不同的药物，保证药物终浓度由下到上梯度递减，每种处理两个重复。最后，上机检测。仪器读值反映胞内β-arrestin2上膜情况以及G蛋白三聚体解离情况，前者表征血清素1A受体下游β-arrestin2信号通路的激活程度，后者表征血清素1A受体下游G蛋白信号通路的激活程度，由此，各种化合物对血清素1A受体的激动作用可被揭示。In order to detect the downstream G protein signaling pathway mediated by serotonin 1A receptor, on the first day, 1 μg serotonin 1A receptor, 1 μg Gα i1 containing C-terminal algae luciferase ( Gα i1 -Rluc), 1 μg G β3 , 1 μg G γ9 containing C-terminal green fluorescent protein (G γ9 -GFP), and 16 μL PEI were used for transfection. At the same time, in order to detect the downstream β-arrestin2 signaling pathway mediated by the serotonin 1A receptor, on the first day, 500 ng of the serotonin 1A receptor (5HT 1A R-Rluc) containing C-terminal seaweed luciferase, 500 ng G protein-coupled receptor kinase 2 (GRK 2 ), 2500ng β-arrestin2 (GFP2-ARRB2) containing N-terminal green fluorescent protein and 14 μL PEI were used for transfection. The next day, digest the overgrown cells and plate a 96-well plate with the amount of cells in a 6 cm culture dish full of cells, with 100 μL of medium per well. On the third day, dosing test. Take out the 96-well plate from the cell room to remove the medium, add 40 μL of the substrate coelenterazine 400a (final concentration 5 μM) to each well, and then add 20 μL of different drugs in turn from left to right to ensure that the final drug concentration is from bottom to top Gradient descending, two replicates per treatment. Finally, on-board testing. The reading value of the instrument reflects the situation on the membrane of β-arrestin2 in the cell and the dissociation of the G protein trimer. The former indicates the activation degree of the β-arrestin2 signaling pathway downstream of the serotonin 1A receptor, and the latter indicates the G protein downstream of the serotonin 1A receptor. The degree of activation of signaling pathways, and thus, the agonistic effect of various compounds on the serotonin 1A receptor, can be revealed.
结果如表4所示。The results are shown in Table 4.
结果表明，本发明化合物5-羟色胺1A(5-HT1A)受体有中等到较强的激动活性。The results show that the compound of the present invention has moderate to strong agonistic activity on 5-hydroxytryptamine 1A (5-HT 1A ) receptors.
表4

Table 4

备注：1EC50是在实验中给出半数最大反应的化合物浓度。2括号Emax％表示化合物在实验中产生的最大反应强度(Emax)相对于内源性配体5-羟色胺的百分比。Remarks: 1 The EC50 is the concentration of the compound that gives the half maximal response in the experiment. 2 Brackets E max % represent the percentage of the maximum response intensity (E max ) produced by the compound in the experiment relative to the endogenous ligand 5-hydroxytryptamine.
生物测试例5：本发明化合物对5-HT2A受体的亲和力测试 Biological Test Example 5: Affinity test of compounds of the present invention to 5-HT 2A receptors
本发明化合物对于5-HT2A受体的亲和力采用放射性配体竞争性实验的方法进行测定。第一步，制备含有特定5-HT2A受体的细胞膜组分。10cm培养皿以10ng 5-HT2A受体和40μL PEI进行转染，48小时后，从细胞房拿出10厘米培养皿，其中培养的细胞已表达5-HT2A受体。用真空泵吸掉培液，每孔加入3mL裂解液，将细胞置于4℃冷库，静置10分钟。待细胞脱落后，将其转移到15mL离心管中，4℃离心机1500rpm离心5分钟，弃上清。将细胞沉淀转移到组织匀浆器中，再向其中加入3mL裂解液，充分研磨至细胞破碎。然后，将细胞悬液等分至多个EP管中，4℃离心机12000rpm离心5min，弃上清。沉淀即为含有5-HT2A受体的细胞膜组分。第二步，对瞬时表达5-HT2A受体的293T膜组分进行配体受体结合实验。首先，向含有5-HT2A受体的细胞膜组分加入标准结合缓冲液，用电动组织匀浆器将细胞膜破碎重悬。96孔板每孔加入30μL膜蛋白悬液。然后，96孔板从左到右依次加入30μL不同药物，保证药物终浓度由下到上依次为10-5M、10-6M、10-7M、10-8M、10- 9M、0M，每种处理两个重复。紧接着，96孔板每孔加入30μL[3H]-ketanserin。室温避光孵育2小时。检测。机器读值反应膜上结合[3H]-ketanserin的量，进一步数据处理后得到不同化合物对5-HT2A受体的亲和力Ki值。结果如表3所示。The affinity of the compound of the present invention for the 5-HT 2A receptor is determined by the method of radioligand competition experiment. In the first step, cell membrane fractions containing specific 5-HT 2A receptors are prepared. A 10cm culture dish was transfected with 10ng 5-HT 2A receptor and 40μL PEI. After 48 hours, the 10cm culture dish was taken out from the cell room, in which the cultured cells had expressed the 5-HT 2A receptor. Use a vacuum pump to suck off the culture medium, add 3mL of lysate to each well, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing the 5-HT 2A receptor. In the second step, ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing 5-HT 2A receptors. First, add standard binding buffer to the cell membrane fraction containing the 5-HT 2A receptor, and resuspend the cell membrane with an electric tissue homogenizer. Add 30 μL of membrane protein suspension to each well of a 96-well plate. Then, 30 μL of different drugs were added to the 96 - well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment. Immediately afterwards, 30 μL of [ 3 H]-ketanserin was added to each well of the 96-well plate. Incubate at room temperature for 2 hours in the dark. detection. The machine reading value reflects the amount of [ 3 H]-ketanserin bound on the membrane, and after further data processing, the affinity K i value of different compounds for the 5-HT 2A receptor is obtained. The results are shown in Table 3.
表5table 5
化合物compound Ki,nM(pKi±SEM)K i ,nM(pK i ±SEM)
I-A1I-A1 1793nM(5.74±0.03)1793nM (5.74±0.03)
I-A2I-A2 1107nM(5.95±0.05)1107nM(5.95±0.05)
I-A16I-A16 1320nM1320nM
I-A20I-A20 1307nM1307nM
I-A21I-A21 >10000nM>10000nM
I-A28I-A28 >10000nM>10000nM
I-A29I-A29 5524nM5524nM
I-B7I-B7 3514nM3514nM
阿立哌唑Aripiprazole 42.2nM42.2nM
卡利拉嗪Cariprazine 62.9nM62.9nM
本发明化合物对5-HT2A受体的亲和力很弱，具有D2受体、5-HT1A受体相对于5-HT2A受体的选择性。表5结果表明，化合物I-A1、I-A2、I-A16、I-A20、I-A21、I-A28、I-A29和I-B7对5-HT2A受体的亲和力很弱。对比表1的数据，可见本发明的化合物具有很好的D2受体相对于5-HT2A受体的选择性。 The compound of the present invention has very weak affinity to 5-HT 2A receptors, and has selectivity for D2 receptors and 5-HT 1A receptors relative to 5-HT 2A receptors. The results in Table 5 show that compounds I-A1, I-A2, I-A16, I-A20, I-A21, I-A28, I-A29 and I-B7 have very weak affinity to the 5-HT 2A receptor. Comparing the data in Table 1, it can be seen that the compounds of the present invention have good selectivity for D2 receptors relative to 5-HT 2A receptors.
生物测试例6：本发明化合物的大鼠药代动力学性质测试Biological test example 6: Rat pharmacokinetic property test of the compound of the present invention
化合物经灌胃和静脉注射单次给予SD大鼠的药代动力学性质测试Pharmacokinetic properties test of compounds administered to SD rats by intragastric administration and intravenous injection
(1)实验目的(1) Purpose of the experiment
化合物单剂量给予雄性SD大鼠后，于不同时间点采集血样，LC-MS/MS测定大鼠血浆中化合物的浓度并计算相关药代参数，考察化合物在大鼠体内药代动力学情况。After a single dose of the compound was administered to male SD rats, blood samples were collected at different time points, and the concentration of the compound in rat plasma was determined by LC-MS/MS, and relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetics of the compound in the rat.
(2)实验方法(2) Experimental method
雄性SD大鼠由苏州昭衍实验动物有限责任公司提供。SD大鼠给药前1天禁食不禁水12～14h，给药后4h给食。Male SD rats were provided by Suzhou Zhaoyan Experimental Animal Co., Ltd. SD rats were fasted without water for 12-14 hours one day before administration, and fed 4 hours after administration.
每个化合物的分为静脉注射给药和灌胃给药两组，每组3只大鼠。静脉给药(给药剂量3mg/kg，给药浓度为0.6mL/kg)和灌胃给药(给药剂量10mg/kg，给药浓度为1mL/kg)，均以5％DMSO+5％Solutol+90％生理盐水为溶媒。Each compound was divided into two groups for intravenous injection and intragastric administration, with 3 rats in each group. Intravenous administration (administration dose 3mg/kg, administration concentration is 0.6mL/kg) and intragastric administration (administration dose 10mg/kg, administration concentration is 1mL/kg), all with 5%DMSO+5% Solutol+90% normal saline is the vehicle.
样品采集：每只动物每次通过眼眶取0.10mL血液，EDTAK2抗凝，采集时间点为IV/PO组：给予受试物后5,15,30min,1,2,4,6,8,24h。血液样本采集后置于冰上，并于30分钟之内离心分离血浆(离心条件：5000转/分钟，10分钟，4℃)。分析前存放于–80℃。Sample collection: 0.10mL blood is taken from each animal through the orbit each time, anticoagulated with EDTAK 2 , and the collection time point is IV/PO group: 5, 15, 30min, 1, 2, 4, 6, 8, after administration of the test substance 24h. The blood samples were placed on ice after collection, and the plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). Store at –80°C until analysis.
数据处理：数据采集及控制系统软件为Analyst1.5.1软件(Applied Biosystem)。图谱样品峰积分方式为自动积分；采用样品峰面积和内标峰面积的比值作为指标，和样品的浓度进行回归。回归方式：线性回归，权重系数为1/X2。药代动力学参数用WinNonlin Professional v6.3(Pharsight,USA)用非房室模型分析处理。Cmax为实测的最大血药浓度，血药浓度-时间曲线下面积AUC(0→t)由梯形法计算得到，tmax为给药后血药浓度达峰时间。实验数据用“均数±标准差”(Mean±SD,n≥3)或“均数”(Mean,n＝2)表示。Data processing: The data acquisition and control system software is Analyst1.5.1 software (Applied Biosystem). The peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as the index, and the concentration of the sample is used for regression. Regression method: linear regression, the weight coefficient is 1/X 2 . Pharmacokinetic parameters were analyzed with WinNonlin Professional v6.3 (Pharsight, USA) using non-compartmental models. C max is the measured maximum blood drug concentration, the area under the blood drug concentration-time curve AUC (0→t) is calculated by the trapezoidal method, and t max is the peak time of blood drug concentration after administration. The experimental data are expressed by "mean ± standard deviation" (Mean ± SD, n≥3) or "mean" (Mean, n=2).
(3)实验结果(3) Experimental results
本发明化合物的SD大鼠代谢性质如表6-8所示。从表6-8所列数据可以看出，本发明化合物在SD大鼠体内具有良好的药代动力学性质、合理的半衰期和良好的口服生物利用度。The SD rat metabolic properties of the compounds of the present invention are shown in Table 6-8. It can be seen from the data listed in Tables 6-8 that the compounds of the present invention have good pharmacokinetic properties, reasonable half-life and good oral bioavailability in SD rats.
表6：化合物I-A1和I-A12的大鼠代谢性质

Table 6: Rat metabolic properties of compounds I-A1 and I-A12

表7：化合物I-B7和I-C1的大鼠代谢性质
Table 7: Rat metabolic properties of compounds I-B7 and I-C1
表8：化合物I-C2和I-C7的大鼠代谢性质
Table 8: Rat metabolic properties of compounds I-C2 and I-C7
备注：“--”表示不适用。Note: "--" means not applicable.
生物测试例7：化合物腹腔注射单次给予C57雄性小鼠的脑透过率测试Biological Test Example 7: Brain permeability test of C57 male mice given a single intraperitoneal injection of the compound
采用与药代动力学实验一致的方法，分别在0.5，2.0，4.0小时每只动物通过眼眶取0.030mL血液，EDTA-K2抗凝，血液样本采集后置于冰上，并于30分钟之内离心分离血浆(离心条件：5000转/分钟，10分钟，4℃)，分析前存放于–80℃。动物放血安乐死后取脑组织样品，用50％甲醇按照体重1：3匀浆(m/v＝1:3)，匀浆液分析前存放于–80℃。以LC/MS/MS方法分析血浆和脑组织中的药物浓度并进行比较。Using the same method as the pharmacokinetic experiment, 0.030 mL of blood was collected from each animal through the orbit at 0.5, 2.0, and 4.0 hours, anticoagulated with EDTA-K2, and the blood samples were collected and placed on ice, and within 30 minutes Plasma was separated by centrifugation (centrifugation conditions: 5000 rpm, 10 minutes, 4°C), and stored at –80°C before analysis. Brain tissue samples were taken after animals were euthanized by bloodletting, homogenized with 50% methanol at a ratio of 1:3 to body weight (m/v=1:3), and the homogenate was stored at –80°C before analysis. The drug concentrations in plasma and brain tissue were analyzed and compared by LC/MS/MS.
化合物血浆和脑组织药物浓度及比值如表9所示。从表9可以看出，本发明的化合物具有良好的透脑性质。The drug concentrations and ratios of the compounds in plasma and brain tissue are shown in Table 9. It can be seen from Table 9 that the compounds of the present invention have good brain-penetrating properties.
表9：本发明化合物的小鼠脑透性质Table 9: Mouse brain permeation properties of compounds of the present invention
 the I-A1I-A1 I-A12I-A12 I-B7I-B7 I-C1I-C1 I-C2I-C2 I-C7I-C7
0.5h脑0.5h brain 1106±431106±43 1399±2201399±220 392±15392±15 1943±631943±63 2805±2082805±208 1026±961026±96
0.5h血浆0.5h plasma 2215±4472215±447 830±119830±119 598±19598±19 4062±3674062±367 3282±4563282±456 336±28336±28
0.5h比值0.5h ratio 0.4990.499 1.691.69 0.6560.656 0.4780.478 0.8550.855 3.053.05
2.0h脑2.0h brain 236±25236±25 455±61455±61 73.0±12973.0±129 732±56732±56 1256±2791256±279 714±143714±143
2.0h血浆2.0h plasma 397±26.3397±26.3 202±56.2202±56.2 114±67.9114±67.9 1103±891103±89 1506±5451506±545 267±47267±47
2.0h比值2.0h ratio 0.5940.594 2.262.26 0.6430.643 0.6630.663 0.8340.834 2.672.67
4.0h脑4.0h brain ---- ---- ---- 161±55161±55 599±54599±54 491±80491±80
4.0h血浆4.0h plasma ---- ---- ---- 297±106297±106 558±100558±100 219±15219±15
4.0h比值4.0h ratio ---- ---- ---- 0.5410.541 0.9310.931 2.242.24
AUC脑AUC Brain ---- ---- ---- 33853385 55615561 27672767
AUC血浆AUC plasma ---- ---- ---- 62896289 65176517 10221022
AUC比值AUC ratio ---- ---- ---- 0.5380.538 0.8530.853 2.712.71
备注：腹腔注射给药,5mg/kg,溶媒5％DMSO+95％生理盐水；“--”未测试；血浆和脑内化合物浓度单位为ng/mL；AUC单位为hr·ng/mL。Remarks: intraperitoneal injection, 5 mg/kg, vehicle 5% DMSO+95% saline; "--" not tested; plasma and brain compound concentration unit is ng/mL; AUC unit is hr·ng/mL.
生物测试例8：化合物对于精神分裂症样动物行为学模型的药效测试Biological test example 8: Drug efficacy test of compounds on schizophrenia-like animal behavior models
空场运动能力测试open field athletic ability test
实验方法：实验动物为C57B6雄鼠，每组n＝8。此模型以C57B6小鼠为实验动物，通过急性注射NMDA拮抗剂MK801，诱导小鼠在空场环境中产生运动机能亢进的行为表征建模，用以检测不同化合物对MK801诱导的运动机能亢进表型的抑制效果。所有小鼠行为实验在小鼠的光照期进行，实验通过摄像头全程记录并通过行为学跟踪软件进行自动跟踪及进行数据统计。化合物通过腹腔注射给 药，注射完成后，小鼠立刻进入空场并开始记录运动轨迹，30分钟后，小鼠通过腹腔注射接受0.2mg/kg的MK801，并在给药后立刻回到空场继续记录120分钟的运动轨迹。小鼠的累计移动距离按照每五分钟为一个数据采样点进行统计。数据统计使用Student-t-test进行，p<0.05为*，p<0.01为**，p<0.001为***，p<0.0001为****。不同剂量的本发明化合物与MK801(0.2mg/kg)联合作用下小鼠0-45分钟内的总移动距离见表10。Experimental method: the experimental animals are C57B6 male mice, n=8 in each group. This model uses C57B6 mice as experimental animals, through acute injection of NMDA antagonist MK801, to induce the behavioral characterization of hyperkinesia in the open field environment, and to test the effect of different compounds on the hyperkinesia phenotype induced by MK801 inhibitory effect. All mouse behavior experiments were carried out during the light period of the mice, and the experiment was recorded through the camera and automatically tracked and counted by the behavioral tracking software. The compound was given by intraperitoneal injection After the injection was completed, the mice immediately entered the empty field and began to record the movement trajectory. After 30 minutes, the mice received 0.2mg/kg of MK801 by intraperitoneal injection, and returned to the empty field immediately after the administration to continue recording 120 minutes. motion track. The accumulative moving distance of the mice was counted as a data sampling point every five minutes. Data statistics are carried out using Student-t-test, p<0.05 is *, p<0.01 is **, p<0.001 is ***, p<0.0001 is ****. See Table 10 for the total moving distance of mice within 0-45 minutes under the combined action of different doses of the compound of the present invention and MK801 (0.2 mg/kg).
表10：本发明化合物对MK-801诱导的小鼠高自发活动的抑制活性
Table 10: Inhibitory activity of compounds of the present invention on MK-801-induced hyperspontaneous activity in mice
表10所示的空场运动能力检测结果表明，本发明化合物I-A1，I-A12和I-B7等在不同剂量下能够显著抑制MK801所诱导的小鼠高自发活动。 The test results of open field exercise ability shown in Table 10 show that the compounds I-A1, I-A12 and I-B7 of the present invention can significantly inhibit the high spontaneous activity of mice induced by MK801 at different doses.

Claims (15)

  1. 一种式I所示的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，
    A compound represented by formula I, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof,
    其中，in,
    X为N、O、NRa或CRb；X is N, O, NR a or CR b ;
    Y为C或N；Y is C or N;
    为双键或者单键； is a double bond or a single bond;
    Ra和Rb各自独立地为H或C1-C6烷基；R a and R b are each independently H or C 1 -C 6 alkyl;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
    Rc和Rd各自独立地为H或C1-C6烷基；R c and R d are each independently H or C 1 -C 6 alkyl;
    m、n1和n2各自独立地为1、2、3、4、5或6；m, n1 and n2 are each independently 1, 2, 3, 4, 5 or 6;
    M为不存在、-O-或-NH-C(O)-；M is absent, -O- or -NH-C(O)-;
    环Q为饱和或部分不饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；Ring Q is a saturated or partially unsaturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or an 8-11 membered Bicyclocyclic rings; one ring in the 8-11 membered bicyclocyclic rings is a saturated or partially unsaturated 5-7-membered carbocycle, or a saturated or partially unsaturated 5-7-membered heterocyclic ring, and the other One ring is a benzene ring or a 5-6 membered heteroaromatic ring;
    R1为C1-C6烷基或卤代C1-C6烷基；R 1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
    R2各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基或卤代C1-C6烷氧基；R 2 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl or halogenated C 1 -C 6 alkoxy;
    R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、-NH-C(O)Re或-NH-S(O)2Re；R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 Alkoxy, -NH-C(O)R e or -NH-S(O) 2 R e ;
    或者，两个R3与其相连的原子形成3-8元的环烷基；Alternatively, two R 3 form a 3-8 membered cycloalkyl group with the atoms connected to them;
    Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
    Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
    R4为氧代(＝O)； R is oxo (=O);
    p、q和r各自独立地为0、1、2、3或4；p, q and r are each independently 0, 1, 2, 3 or 4;
    所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S。The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is 1, 2 or 3 each independently, and each of the heteroatoms is N, O or S independently.
  2. 如权利要求1所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，Ra和Rb为H； The compound according to claim 1, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereomer, tautomer or solvate thereof, wherein R a and R b is H;
    和/或，Rc和Rd为H；And/or, R c and R d are H;
    和/或，m为1、2、3或4；and/or, m is 1, 2, 3 or 4;
    和/或，n1和n2为1；And/or, n1 and n2 are 1;
    和/或，M中，-NH-C(O)-的氮原子与L相连；And/or, in M, the nitrogen atom of -NH-C(O)- is connected to L;
    和/或，R1各自独立地为甲基、乙基或异丙基；And/or, each R is independently methyl, ethyl or isopropyl;
    和/或，R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；较佳地，R3各自独立地为C1-C6烷基或-NH-C(O)Re；And/or, R 3 is each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; Preferably, each R 3 is independently C 1 -C 6 alkyl or -NH-C(O)R e ;
    和/或，p为0；and/or, p is 0;
    和/或，环Q通过C原子与M相连；And/or, the ring Q is connected to M through a C atom;
    和/或，环Q中，所述3-8元的碳环为4、5、6或7元的碳环；And/or, in the ring Q, the 3-8 membered carbocycle is a 4, 5, 6 or 7 membered carbocycle;
    和/或，环Q中，所述3-8元的杂环为6元的杂环；And/or, in the ring Q, the 3-8-membered heterocycle is a 6-membered heterocycle;
    和/或，环Q中，所述3-8元的杂环中的杂原子为N或O，例如N；And/or, in the ring Q, the heteroatom in the 3-8 membered heterocycle is N or O, such as N;
    和/或，环Q中，所述6-10元的芳环为苯环；And/or, in the ring Q, the 6-10 membered aromatic ring is a benzene ring;
    和/或，环Q中，所述5-10元杂芳环中的杂原子个数1或2个；和/或，环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环，其中所述5-7元的杂环和5-6元的杂芳环中的杂原子个数独立地为1或2个，杂原子为N。And/or, in ring Q, the number of heteroatoms in the 5-10 membered heteroaromatic ring is 1 or 2; and/or, in ring Q, one ring in the 8-11 membered bicyclic ring is A saturated or partially unsaturated 5-7 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the 5-7 membered heterocyclic ring and the 5-6 membered heteroaromatic ring The number of heteroatoms is independently 1 or 2, and the heteroatoms are N.
  3. 如权利要求1或2所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，L为-(CH2)-、-(CH2)2-、-(CH2)3-、-(CH2)4-或-(CH2)-CH＝CH-(CH2)-；The compound as claimed in claim 1 or 2, or its pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate, is characterized in that, L is -(CH 2 )-, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 )-CH=CH-(CH 2 )-;
    和/或，环Q为 And/or, ring Q is
  4. 如权利要求1至3中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，为
    The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that, for
    和/或，q为0、1或2；And/or, q is 0, 1 or 2;
    和/或，r为0、1或2。And/or, r is 0, 1 or 2.
  5. 如权利要求1至4中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，为 其中，R3-1为R3，R3-2为H或R3。The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that, for Wherein, R 3-1 is R 3 , and R 3-2 is H or R 3 .
  6. 如权利要求1至5中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，为 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that, for
    较佳地，为以下任一方案：Preferably, for any of the following options:
    方案(1)：为
    plan 1): for
    方案(2)：为 Scenario 2): for
    方案(3)：为 Scheme (3): for
    方案(4)：为 Scheme (4): for
    方案(5)：为 Scheme (5): for
    方案(6)：为 Scheme (6): for
  7. 如权利要求1至6中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，L和M的定义为以下任一种情况：The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that L and M are defined as any of the following situations:
    (1)L为-(CRcRd)2-，M为不存在或-NH-C(O)-；(1) L is -(CR c R d ) 2 -, M is absent or -NH-C(O)-;
    (2)L为-(CRcRd)3-，M为-O-或不存在；(2) L is -(CR c R d ) 3 -, M is -O- or does not exist;
    (3)L为-(CRcRd)4-，M为-O-或不存在；(3) L is -(CR c R d ) 4 -, M is -O- or does not exist;
    (4)L为-(CRcRd)-CH＝CH-(CRcRd)-，M为-O-； (4) L is -(CR c R d )-CH=CH-(CR c R d )-, M is -O-;
    (5)L为-(CRcRd)-，M为不存在。(5) L is -(CR c R d )-, and M is absent.
  8. 如权利要求1至7中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，所述化合物具有如下任一结构：
    The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that the compound has any of the following structures:
    其中，L、M、环Q、R1、R2、R3、R4、p、q和r的定义如权利要求1至7中任一项所述。Wherein, the definitions of L, M, ring Q, R 1 , R 2 , R 3 , R 4 , p, q and r are as described in any one of claims 1 to 7.
  9. 如权利要求1至8中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，所述化合物为如下任一种情况：The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that the compound is any of the following:
    ①环Q中，所述3-8元的碳环为5-8元的碳环或4-6元碳环，所述5-8元的碳环优选为5-7元碳环，例如6-7元碳环；① In the ring Q, the 3-8 membered carbocycle is a 5-8 membered carbocycle or a 4-6 membered carbocycle, and the 5-8 membered carbocycle is preferably a 5-7 membered carbocycle, for example, 6 -7-membered carbon ring;
    ②环Q中，所述3-8元的杂环为含氮6元杂环，例如六氢吡啶；② In ring Q, the 3-8 membered heterocycle is a nitrogen-containing 6-membered heterocycle, such as hexahydropyridine;
    ③环Q中，所述5-10元杂芳环为 ③ In Ring Q, the 5-10 membered heteroaromatic ring is
    ④环Q中，所述8-11元的双环并环为8-10元的双环并环；④ In the ring Q, the 8-11-membered double-ring combination is an 8-10-membered double-ring combination;
    ⑤环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环里的5-7元的杂环为5-6元杂环，例如6元杂环；⑤ In the ring Q, one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered heterocycle, and the 5-7-membered heterocycle is a 5-6-membered heterocycle, for example 6-membered heterocycle;
    ⑥环Q中，所述8-11元的双环并环中一个环为饱和或部分不饱和的5-7元的杂环里的5-7元的杂环至多含有一个N原子或至多含有一个氧原子；⑥ In the ring Q, the 5-7 membered heterocycle in the 8-11 membered bicyclic ring is saturated or partially unsaturated, and the 5-7 membered heterocycle contains at most one N atom or at most one Oxygen atom;
    ⑦L为-(CRcRd)2-，环Q中，所述8-11元的双环并环中的饱和或部分不饱和的5-7元的杂环中至多含有一个N；⑦L is -(CR c R d ) 2 -, in the ring Q, the saturated or partially unsaturated 5-7 membered heterocyclic ring in the 8-11 membered bicyclic ring contains at most one N;
    ⑧L为-(CRcRd)4-，M为-O-，所述8-11元的双环并环中的苯环或5-6元的杂芳环为5-6元芳杂环；⑧L is -(CR c R d ) 4 -, M is -O-, and the benzene ring or the 5-6 membered heteroaromatic ring in the 8-11 membered bicyclic ring is a 5-6 membered aromatic heterocycle;
    ⑨环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；⑨ Ring Q is a saturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or an 8-11 membered bicyclic ring and ring; one ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is A benzene ring or a 5-6 membered heteroaryl ring;
    ⑩环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环。⑩ Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, phenyl, a 5-10-membered heteroaromatic ring or an 8-10-membered bicyclic ring; the 8 -One ring in the 10-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocyclic ring, or a saturated or partially unsaturated 5-6-membered heterocyclic ring, and the other ring is a benzene ring or a 5- 6-membered heteroaromatic ring.
  10. 如权利要求1至9中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异 构体、非对映异构体、互变异构体或溶剂化物，其特征在于，The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer isomers, diastereoisomers, tautomers or solvates, characterized in that
    所述的化合物为以下任一方案：Described compound is any of the following schemes:
    方案(1)：plan 1):
    X为N、O、NRa或CRb；X is N, O, NR a or CR b ;
    Y为C或N；Y is C or N;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
    Rc和Rd各自独立地为H； Rc and Rd are each independently H;
    m为1、2、3或4；m is 1, 2, 3 or 4;
    n1和n2为1；n1 and n2 are 1;
    P为0；P is 0;
    r为0、1或2；r is 0, 1 or 2;
    q为0、1或2；q is 0, 1 or 2;
    M为不存在、-O-或-NH-C(O)-；M is absent, -O- or -NH-C(O)-;
    环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、6-10元的芳环、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, a 6-10-membered aromatic ring, a 5-10-membered heteroaromatic ring or an 8-11-membered bicyclic ring ; One ring in the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is benzene Ring or 5-6 membered heteroaromatic ring;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    R3各自独立地为F、Cl、Br、I、羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；较佳地，R3各自独立地为羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；或者，两个R3与其相连的原子形成3-8元的环烷基；R 3 are each independently F, Cl, Br, I, hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; preferably, R 3 are each independently hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 are connected to the atom to form 3-8 Cycloalkyl;
    Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
    Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
    R4为氧代(＝O)； R is oxo (=O);
    所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
    方案(2)：Scenario 2):
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;
    Rc和Rd各自独立地为H； Rc and Rd are each independently H;
    m为1、2、3或4；m is 1, 2, 3 or 4;
    n1和n2为1；n1 and n2 are 1;
    P为0；P is 0;
    r为0、1或2；r is 0, 1 or 2;
    q为0、1或2；q is 0, 1 or 2;
    M为不存在、-O-或-NH-C(O)-； M is absent, -O- or -NH-C(O)-;
    环Q为饱和的3-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环；所述8-10元的双环并环中的饱和或部分不饱和的5-6元的杂环里的5-6元的杂环含一个氧原子、一个氮原子、两个氮原子、或、一个氧原子和一个氮原子；Ring Q is a saturated 3-8-membered carbocycle, a saturated or partially unsaturated 3-8-membered heterocycle, phenyl, a 5-10-membered heteroaromatic ring or an 8-10-membered bicyclic ring; the 8- One of the 10-membered bicyclic rings is a saturated or partially unsaturated 5-7-membered carbocyclic ring, or a saturated or partially unsaturated 5-6-membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, two nitrogen atoms, or, an oxygen atom and a nitrogen atom;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    R3为羟基、C1-C6烷基、-NH-C(O)Re或-NH-S(O)2Re；或者，两个R3与其相连的原子形成3-8元的环烷基；R 3 is hydroxyl, C 1 -C 6 alkyl, -NH-C(O)R e or -NH-S(O) 2 R e ; or, two R 3 and the atoms connected to it form a 3-8 membered Cycloalkyl;
    Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
    Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
    R4为氧代(＝O)； R is oxo (=O);
    所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
    方案(3)：Scheme (3):
    X为N或O；X is N or O;
    Y为C；Y is C;
    P为0；P is 0;
    r为0、1或2；r is 0, 1 or 2;
    q为0、1或2；q is 0, 1 or 2;
    L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2、3或4；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
    m为2时，M为不存在或-NH-C(O)-，环Q为饱和的5-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-7元的杂环，另一个环为苯环或5-6元的杂芳环；When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-7 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
    m为3时，M为不存在；环Q为部分不饱和的3-8元的杂环或8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的杂环，另一个环为苯环；When m is 3, M does not exist; Ring Q is a partially unsaturated 3-8 membered heterocycle or 8-11 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-7 membered heterocyclic ring, the other ring is a benzene ring;
    m为4时，M为-O-，环Q为8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-7元的杂环，另一个环为5-6元的杂芳环；When m is 4, M is -O-, and ring Q is an 8-11-membered bicyclic ring; one ring in the 8-11-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
    或m为4时，M为不存在；Or when m is 4, M does not exist;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    R3各自独立地为F、Cl、Br、I、C1-C6烷基或-NH-C(O)Re；较佳地，R3各自独立地为F、Cl、Br、I、C1-C6烷基或-NH-C(O)Re；或者，两个R3与其相连的原子形成3-8元的环烷基；Each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O) Re ; preferably, each R 3 is independently F, Cl, Br, I, C 1 -C 6 alkyl or -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
    Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
    Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
    R4为氧代(＝O)； R is oxo (=O);
    所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
    所述8-11元的双环并环中的饱和或部分不饱和的5-7元的杂环里的5-7元的杂环含一个氧原子、一个氮原子、两个氧原子、或、一个氧原子和一个氮原子；The 5-7 membered heterocycle in the saturated or partially unsaturated 5-7 membered heterocycle in the 8-11 membered bicyclic ring contains one oxygen atom, one nitrogen atom, two oxygen atoms, or, an oxygen atom and a nitrogen atom;
    方案(4)：Scheme (4):
    X为N或O；X is N or O;
    Y为C；Y is C;
    P为0；P is 0;
    r为0、1或2；r is 0, 1 or 2;
    q为0、1或2；q is 0, 1 or 2;
    L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2、3或4；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;
    m为2时，M为不存在或-NH-C(O)-，环Q为饱和的5-8元碳环、饱和或部分不饱和的3-8元的杂环、苯基、5-10元杂芳环或8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-7元的碳环、或饱和或部分不饱和的5-6元的杂环，另一个环为苯环或5-6元的杂芳环；When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 5-8 membered carbocycle, a saturated or partially unsaturated 3-8 membered heterocycle, phenyl, 5- 10-membered heteroaromatic ring or 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-7-membered carbocycle, or saturated or partially unsaturated A 5-6 membered heterocyclic ring, the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;
    m为3时，M为不存在，环Q为部分不饱和的3-8元的杂环或8-10元的双环并环；所述8-11元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为苯环；When m is 3, M does not exist, ring Q is a partially unsaturated 3-8 membered heterocycle or 8-10 membered bicyclic ring; one ring in the 8-11 membered bicyclic ring is saturated Or a partially unsaturated 5-6 membered heterocyclic ring, the other ring is a benzene ring;
    m为4时，M为-O-，环Q为8-10元的双环并环；所述8-10元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为5-6元的杂芳环；When m is 4, M is -O-, and ring Q is an 8-10-membered bicyclic ring; one ring in the 8-10-membered bicyclic ring is a saturated or partially unsaturated 5-6-membered hetero Ring, the other ring is a 5-6 membered heteroaromatic ring;
    或m为4时，M为不存在；环Q为饱和或部分不饱和的3-8元的杂环或8-10元的双环并环；所述8-6元的双环并环中的一个环为饱和或部分不饱和的5-6元的杂环，另一个环为苯环；Or when m is 4, M does not exist; the ring Q is a saturated or partially unsaturated 3-8 membered heterocycle or an 8-10 membered bicyclic ring; one of the 8-6 membered bicyclic rings The ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    R3各自独立地为C1-C6烷基、-NH-C(O)Re；或者，两个R3与其相连的原子形成3-8元的环烷基；Each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e ; or, two R 3 and the atoms connected to it form a 3-8 membered cycloalkyl group;
    Re为C1-C6烷基、-NH2、-NHRg、-NRfRg或5-6元的杂芳基；R e is C 1 -C 6 alkyl, -NH 2 , -NHR g , -NR f R g or 5-6 membered heteroaryl;
    Rf和Rg各自独立地为C1-C6烷基；R f and R g are each independently C 1 -C 6 alkyl;
    R4为氧代(＝O)； R is oxo (=O);
    所述的杂环、杂芳环和杂芳基中的杂原子个数各自独立地为1、2或3个，所述杂原子各自独立地为N、O或S；The number of heteroatoms in the heterocycle, heteroaryl ring and heteroaryl is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;
    所述8-10元的双环并环中的饱和或部分不饱和的5-6元的杂环里的5-6元的杂环含一个氧原子、一个氮原子、或、一个氧原子和一个氮原子；The 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in the 8-10 membered bicyclic ring contains an oxygen atom, a nitrogen atom, or, an oxygen atom and an Nitrogen atom;
    方案(5)：Scheme (5):
    X为O；Y为C；P为0；X is O; Y is C; P is 0;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为1、2、3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 1, 2 , 3 or 4;
    L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
    L为-(CRcRd)m-，m为1时，M为不存在，环Q为饱和的6元碳环，R3为羟基；L is -(CR c R d ) m -, when m is 1, M does not exist, the ring Q is a saturated 6-membered carbon ring, and R 3 is a hydroxyl group;
    L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的3-8元碳环、六氢吡啶、噻吩、苯基，R3各自独立地为C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 3-8 membered carbocycle, hexahydropyridine, thiophene, benzene group, each R 3 is independently a C 1 -C 6 alkyl group, -NH-C(O)R e , and R e is a C 1 -C 6 alkyl group;
    L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
    L为-(CRcRd)m-，m为4时，M为-O-或不存在，环Q为六氢吡啶、 L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine,
    环Q为六氢吡啶时，R3各自独立地为C1-C6烷基；When ring Q is hexahydropyridine, each R 3 is independently C 1 -C 6 alkyl;
    环Q为时，q为0；Ring Q is When , q is 0;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    方案(6)：Scheme (6):
    X为N；Y为C；P为0；X is N; Y is C; P is 0;
    L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2或3；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 3;
    L为-(CRcRd)m-，m为2时，M为不存在，环Q为饱和的5-7元碳环，R3各自独立地为-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 5-7 membered carbon ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
    L为-(CRcRd)m-，m为3时，M为-O-，环Q为q为0；L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
    R1为甲基；R 1 is methyl;
    方案(7)：Scheme (7):
    X为C；Y为N；P为0；X is C; Y is N; P is 0;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 3 or 4 ;
    L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
    L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
    L为-(CRcRd)m-，m为4时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
    方案(8)：Scheme (8):
    X为O；Y为C；P为0； X is O; Y is C; P is 0;
    L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2或4；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 4;
    L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的6-7元碳环、苯基、8-11元的双环并环；所述8-11元的双环并环中的一个环为饱和的5-7元的杂环，另一个环为5-6元的杂芳环；所述5-6元的杂芳环含有一个或两个氮原子；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 6-7-membered carbocycle, phenyl, 8-11-membered Bicyclic rings; one ring in the 8-11-membered bicyclic rings is a saturated 5-7-membered heterocyclic ring, and the other ring is a 5-6-membered heteroaromatic ring; the 5-6-membered Heteroaromatic rings contain one or two nitrogen atoms;
    L为-(CRcRd)m-，m为4时，M为不存在或-O-；L is -(CR c R d ) m -, when m is 4, M is absent or -O-;
    L为-(CRcRd)m-，m为4，M为不存在时，环Q为部分不饱和的6元杂环或 L is -(CR c R d ) m -, m is 4, and when M is absent, ring Q is a partially unsaturated 6-membered heterocyclic ring or
    环Q为部分不饱和的6元杂环时，所述部分不饱和的6元杂环中杂原子为氮原子，杂原子个数各自独立地为1、2或3个；When the ring Q is a partially unsaturated 6-membered heterocyclic ring, the heteroatom in the partially unsaturated 6-membered heterocyclic ring is a nitrogen atom, and the number of heteroatoms is 1, 2 or 3 independently;
    L为-(CRcRd)m-，m为4，M为-O-时，环Q为部分不饱和的6元杂环或 When L is -(CR c R d ) m -, m is 4, and M is -O-, ring Q is a partially unsaturated 6-membered heterocyclic ring or
    R3各自独立地为F、C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基；R 3 are each independently F, C 1 -C 6 alkyl, -NH-C(O)R e , Re is C 1 -C 6 alkyl;
    方案(9)：Scheme (9):
    X为O；Y为C；P为0；X is O; Y is C; P is 0;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为2或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 2 or 4 ;
    L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
    L为-(CRcRd)m-，m为2时，M为不存在或-NH-C(O)-，环Q为饱和的4-6元碳环、噻吩、苯基，R3各自独立地为C1-C6烷基、-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-6 membered carbocycle, thiophene, phenyl, R 3 Each is independently C 1 -C 6 alkyl, -NH-C(O)R e , Re is C 1 -C 6 alkyl;
    L为-(CRcRd)m-，m为4时，M为-O-或不存在，环Q为六氢吡啶、 q为0；L is -(CR c R d ) m -, when m is 4, M is -O- or does not exist, ring Q is hexahydropyridine, q is 0;
    R1为C1-C6烷基；R 1 is C 1 -C 6 alkyl;
    方案(10)：Scheme (10):
    X为N；Y为C；P为0；X is N; Y is C; P is 0;
    L为-(CRcRd)m-；Rc和Rd各自独立地为H；m为2或3；L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 3;
    L为-(CRcRd)m-，m为2时，M为不存在，环Q为饱和的6元碳环，R3各自独立地为-NH-C(O)Re，Re为C1-C6烷基；L is -(CR c R d ) m -, when m is 2, M does not exist, ring Q is a saturated 6-membered carbocyclic ring, R 3 is each independently -NH-C(O)R e , R e is C 1 -C 6 alkyl;
    L为-(CRcRd)m-，m为3时，M为-O-，环Q为q为0；L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is q is 0;
    R1为甲基； R 1 is methyl;
    方案(11)：Scheme (11):
    X为C；Y为N；P为0；X is C; Y is N; P is 0;
    L为-(CRcRd)m-或-(CRcRd)n1-CH＝CH-(CRcRd)n2-；Rc和Rd各自独立地为H；m为3或4；L is -(CR c R d ) m -or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 3 or 4 ;
    L为-(CRcRd)n1-CH＝CH-(CRcRd)n2-时，n1和n2为1，M为-O-，环Q为 When L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -, n1 and n2 are 1, M is -O-, and ring Q is
    L为-(CRcRd)m-，m为3时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 3, M is -O-, ring Q is
    L为-(CRcRd)m-，m为4时，M为-O-，环Q为 L is -(CR c R d ) m -, when m is 4, M is -O-, ring Q is
  11. 如权利要求1至10中任一项所述的化合物，或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，其特征在于，所述化合物具有如下任一结构：



    A compound as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof, It is characterized in that the compound has any of the following structures:



  12. 一种式I所示化合物的制备方法，其包括如下步骤：在溶剂中，将式II所示化合物与式III所示化合物进行如下偶联反应，得到式I所示化合物；
    A preparation method of the compound shown in formula I, which comprises the following steps: in a solvent, the compound shown in formula II and the compound shown in formula III are subjected to the following coupling reaction to obtain the compound shown in formula I;
    其中，Hal为卤素；X、Y、L、M、环Q、R1、R2、R3、R4、p、q和r的定义如权利要求1至10中任一项所述。Among them, Hal is a halogen; X, Y, L, M, ring Q, R 1 , R 2 , R 3 , R 4 , p, q and r are as defined in any one of claims 1 to 10.
  13. 一种药物组合物，其包含如权利要求1至11中任一项所述的化合物或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物，和药学上可接受的辅料。A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer Isomers or solvates, and pharmaceutically acceptable excipients.
  14. 一种如权利要求1至11中任一项所述的化合物或其药学上可接受的盐、同位素衍生物、对映异构体、非对映异构体、互变异构体或溶剂化物在制备治疗精神疾病或神经退行性疾病的药物中的用途。A compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt, isotopic derivative, enantiomer, diastereoisomer, tautomer or solvate thereof Use in the preparation of medicines for treating mental illnesses or neurodegenerative diseases.
  15. 如权利要求14所述的用途，其特征在于，所述精神疾病或神经退行性疾病为精神分裂症、抑郁症或帕金森氏症。 The use according to claim 14, characterized in that the mental disease or neurodegenerative disease is schizophrenia, depression or Parkinson's disease.
PCT/CN2023/073216 2022-01-29 2023-01-19 Tricyclic compound, and preparation method therefor and use thereof WO2023143393A1 (en)

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